Compositions and methods for rescuing retinal and choroidal structure and function

Abstract

To provide compositions and methods for rescuing the retinal and choroidal structure and function.SOLUTION: The inventions relate to the use of anti-hemichannel compounds, including anti-connexin 43 hemichannel opening compounds, to rescue or restore the retinal function, to rescue or restore the retinal structure, and / or to rescue or restore the choroidal structure and / or function in chronic retinal and other disorders.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 900,379, filed September 13, 2019, and U.S. Provisional Patent Application No. 62 / 903,504, filed September 20, 2019, both of which are incorporated herein by reference in their entirety.

[0002] The present invention relates generally to the retina and choroid, as well as other ocular processes, and to connexin hemichannels.

[0003] Incorporation by Reference All U.S. patents, U.S. patent application publications, foreign patents, foreign and PCT published applications, articles and other documents, references and publications mentioned herein, as well as all those listed as references cited in all patents published herein, are incorporated herein by reference in their entirety. The incorporated information is made part of this application as if all text and other content were repeated herein, and is treated as part of the text and content of this application as filed. [Background technology]

[0004] The following contains information that may be useful in understanding the present invention. Any information, publication, or document referenced herein, either specifically or implicitly, is not admitted to be prior art or essential to the invention(s) described and claimed herein.

[0005] Diabetes is an increasingly common condition in which the body becomes resistant to the hormone insulin. Diabetes prevents sugar, or glucose, from leaving the bloodstream and entering cells. This condition can lead to serious complications, including an eye-related disease known as diabetic retinopathy.

[0006] When humans experience high blood sugar levels for extended periods, the walls of tiny blood vessels throughout the body thicken. This makes it more difficult for oxygen and important nutrients to move from the blood to the cells that depend on them for survival. One area that is severely affected is the retina, located at the back of the eye. Poor circulation in these small blood vessels can also cause leakage. When blood leaks from small vessels, it becomes trapped within the retina, reducing its ability to convert light waves into vision. Additionally, the thickness of the choroid changes in diabetes and may be related to the severity of retinopathy. The presence of diabetic macular edema is associated with a significant decrease in choroidal thickness. Regatieri See CV, Branchini L, Carmody J, Fujimoto JG, Duker JS, Choroidal thickness in patients with diabetic retinopathy analyzed by spectral-domain optical coherence tomography. Retina. 2012 Mar;32(3):563-8.

[0007] Diabetes-related blood vessel damage dramatically deteriorates the overall health of the retina. Leaked blood clogs the retina, while a lack of nutrients and oxygen causes the retinal tissue to die. Without treatment, vision eventually deteriorates, and eventually the individual loses all vision.

[0008] After 20 years of diabetes, most people have some form of mild diabetic retinopathy. The pathological process in diabetic retinopathy involves retinal microaneurysms and petechial hemorrhages. Dilation and / or hemorrhage of small blood vessels in the underlying choroid can injure receptor cells and retinal neurons, potentially resulting in blindness.

[0009] According to the National Eye Institute (NEI), diabetic retinopathy typically progresses through a series of four stages: (1) Mild Nonproliferative Retinopathy: This stage involves small areas of swelling in the retinal blood vessels, called microaneurysms. (2) Moderate Nonproliferative Retinopathy: As the disease progresses, an ophthalmologist may be able to see swelling and distortion of the retinal blood vessels. At this stage, they may also lose their ability to transport oxygen and nutrients. (3) Severe Nonproliferative Retinopathy: This stage involves worsening vascular blockage, where parts of the retina are deprived of blood. New blood vessels may grow in the blocked areas of the retina. (4) Proliferative Diabetic Retinopathy (PDR): Finally, these new blood vessels grow within the retina, causing leakage, vision loss, and scar tissue formation, which can lead to retinal detachment and blindness.

[0010] Diabetic retinopathy is treated primarily with two methods: injections and laser surgery. Injections involve placing medications, such as corticosteroids or vascular endothelial growth factor (VEGF) antagonists, directly into the eye. Surgically, doctors can use a laser to burn away parts of the retina. Effectively killing these areas allows the limited available blood supply to circulate to the remaining viable tissue, helping to preserve vision.

[0011] Unfortunately, there is no known cure for diabetic retinopathy: the damage caused by blood vessel proliferation, leakage, and oxygen deprivation is permanent, and diabetic retinopathy is not fully reversible with current treatments.

[0012] Despite being an important part of the metabolite delivery system to the outer retina, the choroid remains poorly understood. (Zouache and Luthert, The Choroid in AMD: A Critical Point of Failure? Retina Specialist, January 8, 2018) One of the two major blood sources to the retina, the choroid provides blood to the outer RPE, photoreceptors, and several upper tissue layers. Choroidal insufficiency plays a role in the pathogenesis of age-related macular degeneration (AMD). Choroidal changes have been reported in both early and late AMD. Furthermore, in maculae exhibiting basal lamina deposition, geographic atrophy, and discoid scarring, the vascular density of the choriocapillaris is significantly less than in normal macules. (Zouache and Luthert, supra) Importantly, patients with choroidal changes are at risk for developing retinal vein occlusion. Treatment of abnormal choroidal structure and function is warranted.

[0013] This patent relates to the important discovery of methods and compositions comprising anti-hemichannel compounds that can radically reverse diabetic retinopathy and restore retinal and choroidal structure and function in this and other diseases, disorders, and conditions. [Prior art documents] [Non-patent literature]

[0014] [Non-Patent Document 1] Regatieri CV,Branchini L,Carmody J,Fujimoto JG,Duker JS,Choroidal thickness in patients with diabetic retinopathy analyzed by spectral-domain optical coherence tomography.Retina.2012 Mar;32(3):563-8 Summary of the Invention [Means for solving the problem]

[0015] The invention described and claimed herein has many features and embodiments, including but not limited to those described or referenced in the Summary of the Invention. It is not intended to be all-inclusive, and the invention described and claimed herein is not limited to the features or embodiments identified in the introduction, which are included for illustrative purposes only and not limitation.

[0016] This patent is directed to methods and compositions for the use of anti-hemichannel compounds to restore and improve retinal structure and function. Even a single administration has been found to be effective over a significant period of time. This patent is also directed to methods and compositions for the use of anti-hemichannel compounds to restore and improve choroidal structure and function.

[0017] The data show, for example, that anti-hemichannel compounds can be used to strengthen and restore retinal function, including chronic retinal diseases, conditions, and disorders. In particular, the data show that anti-hemichannel compounds can be used to improve the function of inner retinal photoreceptors and bipolar cells. It also shows, for example, that anti-hemichannel compounds can be used to protect, strengthen, and restore inner retinal cells, improve inner retinal function, improve and restore phototransduction pathways and post-photoreceptor neuronal responses, and improve and restore the structure of retinal layers. It has also been shown that anti-hemichannel compounds can preserve and strengthen the structure of retinal layers as measured by OCT, and that the structure of the choroid can also be improved and restored.

[0018] This patent also covers methods and compositions for the use of anti-hemichannel compounds in reversing chronic ocular diseases previously considered incurable. This patent describes the use of anti-hemichannel compounds to protect and improve, as well as restore and restore, retinal function in chronic ocular diseases, disorders, and conditions in which retinal and / or choroidal damage was previously considered fundamentally irreversible, including, for example, diabetic retinopathy, nonproliferative diabetic retinopathy (designated as NEI stages 1, 2, and / or 3, "mild," "moderate," and "severe" nonproliferative retinopathy), diabetic macular edema, inflammatory or infectious choroiditis, uveitis, age-related macular degeneration (wet and dry), geographic atrophy, and other chronic disorders of the retina characterized in whole or in part by loss of retinal structure and / or function.

[0019] This patent also describes the use of anti-hemichannel compounds to treat choroidal disorders characterized in whole or in part by a loss of choroidal structure and / or function. The methods, compounds, and compositions of the invention can be used to protect and improve, as well as restore and restore, choroidal structure and / or function.

[0020] The patent also describes the use of orally delivered anti-hemichannel compounds to restore retinal function in affected patients, as well as the use of orally delivered anti-hemichannel compounds for the reversal or substantial reversal of chronic retinal disease.

[0021] This patent also describes the use of orally delivered anti-hemichannel compounds for restoring retinal function in patients in need thereof who suffer from chronic eye disease.This patent also describes the use of orally delivered anti-hemichannel compounds for restoring retinal structure in patients in need thereof who suffer from chronic eye disease.

[0022] This patent also provides a method for restoring choroidal structure and function in patients in need thereof. The use of orally delivered anti-hemichannel compounds is also described.

[0023] In another aspect, this patent also covers the use of anti-hemichannel compounds to protect against and reverse diabetic retinopathy that may be present secondary to spontaneous and chronic systemic hyperglycemia.

[0024] The patent also covers methods of using anti-hemichannel compounds for these purposes, including, for example, the benzopyran compound tonabersat (cis-6-acetyl-4S-(3-chloro-4-fluoro-benzoylamino)-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-3S-ol (SB-220453, also known as Xiflam or tonabersat).

[0025] In one aspect, the present invention relates to the use of anti-hemichannel compounds to reverse retinal and choroidal damage, for example, in subjects with diabetes or other conditions characterized in whole or in part by loss of retinal and / or choroidal structure and / or function.

[0026] In one aspect, this patent describes the use of and methods for compounds modulating connexin hemichannels, including connexin 43 hemichannels, to restore or restore retinal function. It also describes the use of and methods for compounds modulating connexin hemichannels, including connexin 43 hemichannels, to restore or restore retinal structure.

[0027] In one aspect, this patent describes the use of and methods for compounds for modulating connexin hemichannels, including connexin 43 hemichannels, to restore or restore choroidal function. It also describes the use of and methods for compounds for modulating connexin hemichannels, including connexin 43 hemichannels, to restore or restore choroidal structure.

[0028] In yet another aspect, the use of anti-hemichannel compounds, including, by way of example, anti-connexin 43 hemichannel opener compounds, is described for preserving choroidal structure and function, preserving retinal structure and function, restoring retinal function, restoring retinal function, and protecting against and reversing diabetic retinopathy secondary to spontaneous and chronic systemic hyperglycemia.

[0029] The methods of the present invention are useful for restoring and restoring choroidal structure and function in subjects, for restoring retinal function, and for protecting against and reversing diabetic retinopathy and macular edema secondary to spontaneous, chronic systemic hyperglycemia, by administering anti-hemichannel compounds to subjects who would benefit therefrom, as well as to subjects with other chronic retinal disorders mentioned herein.

[0030] Another object of the present invention is to provide compounds, compositions, formulations, kits, doses and methods for restoring or restoring retinal structure, restoring retinal function, and / or treating diseases, disorders and conditions that would benefit from the restoration of retinal function.

[0031] Another object of the present invention is to provide compounds, compositions, formulations, kits, doses and methods for restoring or restoring choroidal structure, restoring choroidal function, and / or treating diseases, disorders and conditions that would benefit from the restoration of choroidal function.

[0032] Another object of the present invention is to provide a method for treating diseases, disorders and conditions that would benefit from protection against loss of retinal function. The present invention provides compounds, compositions, formulations, kits and methods for the treatment of cancer and conditions.

[0033] Another object of the present invention is to provide compounds, compositions, formulations, kits and methods for the treatment of diseases, disorders and conditions that benefit from protection against loss of choroidal function.

[0034] In some aspects, the methods of treatment are administered to a mammal, such as a human.

[0035] Anti-hemichannel compounds useful in the present invention include compounds of Formula I, e.g., Xiflam (tonabersat) and / or prodrugs of any of the foregoing compounds, as well as other anti-hemichannel compounds described herein or incorporated by reference herein. In some embodiments, the hemichannel blocker is a small molecule other than Xiflam (tonabersat), e.g., a hemichannel blocker described in Formula I or Formula II of U.S. Patent Application Publication No. 20160177298, filed in the names of Colin Green et al., the disclosure of which is incorporated herein by reference in its entirety.

[0036] Various preferred embodiments include the use of orally available small molecule anti-hemichannel compounds to treat diseases, disorders, and conditions characterized at least in part by loss of retinal and / or choroidal structure or function, or to treat subjects at risk or who may be at risk for loss of retinal and / or choroidal structure or function. In one embodiment, retinal and / or choroidal structure or function is substantially or completely restored by treatment with the described anti-hemichannel compounds, including orally available anti-hemichannel compounds.

[0037] Other preferred embodiments include the use of orally available small molecule anti-hemichannel compounds to treat subjects who are or may be at risk for loss of retinal and / or choroidal structure or function.

[0038] Another aspect of the invention includes a method of improving or restoring choroidal blood flow in a subject having a chronic retinal disorder, the method comprising administering to the subject an effective amount of a hemichannel blocker.

[0039] Another aspect of the invention includes a method of improving or restoring choroidal vascular blood flow to the outer retina in a subject having a chronic retinal disorder, the method comprising administering to the subject an effective amount of a hemichannel blocker.

[0040] Also included are methods for increasing and restoring or restoring residual retinal and / or choroidal function in a subject in need thereof, the methods comprising, for example, administering to the subject a residual-enhancing amount of N-[(3S,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]-3-chloro-4-fluorobenzamide (Xiflam). In some embodiments, the residual-enhancing amount is about 10 to about 200 mg per day. In other embodiments, the residual-enhancing amount is about 20 to about 100 mg per day. These amounts may be administered as a single dose or in divided doses, e.g., BID. Other daily doses, as well as particularly useful weekly, monthly, and implant doses and dosing regimens, have also been developed and are provided herein.

[0041] In some methods, increasing, restoring, or restoring survival treats a chronic retinal disorder. In other embodiments, the chronic retinal disorder is diabetic retinopathy or diabetic macular edema. In other embodiments, the method of increasing survival treats a chronic retinal disorder selected from the group consisting of wet age-related macular degeneration, dry age-related macular degeneration, geographic atrophy, and hypertensive retinopathy.

[0042] In other aspects of the methods of increasing, restoring or restoring survival, the chronic retinal damage is caused by retinal degeneration, edema, diabetes, ischemic retinal degeneration, retinal vascular occlusion, and central retinal vein occlusion.

[0043] In other embodiments of the methods of the present invention, mixed a-wave function and / or improved mixed b-wave function is improved or normalized.

[0044] In another embodiment of the method of the present invention, the function of the PII and PIII rods and cones of the retina is improved.

[0045] In other embodiments of the methods of the present invention, retinal ERG function is improved or normalized.

[0046] In yet another aspect of the methods of the present invention, inner retinal function is improved or normalized.

[0047] In another aspect of the methods of the present invention, photoreceptor function is improved or normalized.

[0048] Also included are methods for increasing, restoring, or restoring survival of retinal structures in a subject in need thereof, comprising administering to the subject 10-200 mg per day, or 1.4 mg / kg per day, or other doses described herein, of N-[(3S,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]-3-chloro-4-fluorobenzamide (Xiflam). In some embodiments, the retinal structures include retinal pigment epithelium, retinal vascular endothelium, and / or retinal layer structures. In other embodiments, microaneurysms and / or giant aneurysms within the retina are reduced.

[0049] Also included are methods for increasing, restoring, or restoring residual choroidal function in a subject in need thereof, comprising administering to the subject 10 to 200 mg per day of N-[(3S,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]-3-chloro-4-fluorobenzamide (Xiflam), or other doses described above or herein. In some embodiments of these methods, choroidal blood flow is improved or normalized. In other embodiments, blood flow in choroidal vessels supplying the outer retina is improved or normalized. In still other embodiments of these methods, regulation of choroidal blood flow is improved or normalized.

[0050] Also claimed herein are methods for increasing choroidal structural survival in a subject in need thereof, comprising administering to the subject 10 to 200 mg per day of N-[(3S,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]-3-chloro-4-fluorobenzamide (Xiflam). In some embodiments of these methods, choroidal thickness is improved. In other embodiments, the choroidal vascular bed is improved or normalized.

[0051] In certain embodiments of the invention, the increase in residual retinal function restores or restores retinal function.

[0052] In another embodiment, the increased survival of retinal structures restores or restores retinal structures.

[0053] In other embodiments, the increased residual choroidal function restores or restores choroidal function.

[0054] In other embodiments, the increased survival of choroidal structures restores or restores choroidal structures.

[0055] In various embodiments, the small molecule that blocks or ameliorates or inhibits hemichannel opening is a prodrug of Xiflam (tonabersat) or an analog thereof.

[0056] In another aspect, the present invention provides the use of a hemichannel blocker in the manufacture of a medicament for use in treating a subject or treating a disease, disorder, or condition described or referenced herein. The medicament comprises, consists essentially of, or consists of an anti-hemichannel compound. In one embodiment, the anti-hemichannel compound is a small molecule anti-hemichannel compound. In another embodiment, the small molecule anti-hemichannel compound is an orally available small molecule anti-hemichannel compound.

[0057] In one embodiment, the pharmaceutical agent comprises, consists essentially of, or consists of a small molecule hemichannel blocker, which is an example of an anti-hemichannel compound. In one embodiment, the pharmaceutical agent comprises, consists essentially of, or consists of a compound according to Formula I or Formula II of U.S. Patent Application Publication 20160177298. In one embodiment, the pharmaceutical agent comprises, consists essentially of, or consists of Xiflam (tonabersat). Formula I: [ka] wherein Y is C-R1; R1 is acetyl; R2 is hydrogen, C 3-8 Cycloalkyl, optionally interrupted by oxygen, or hydroxy, C 1-6 C substituted by alkoxy or substituted aminocarbonyl 1-6 Alkyl, C 1-6 Alkyl carbonyl, C 1-6 Alkoxycarbonyl, C 1-6 Alkylcarbonyloxy, C 1-6 alkoxy, nitro, cyano, halo, trifluoromethyl, or CF3S; or a CF3-A- group, where A is -CF2-, -CO-, -CH2-, CH(OH), SO2, SO, CH2-O, or CONH; or a CF2H-A'- group, where A' is oxygen, sulfur, SO, SO2, CF2, or CFH; trifluoromethoxy, C 1-6 Alkyl sulfinyl, perfluoro C 2-6 Alkylsulfonyl, C 1-6 Alkylsulfonyl, C 1-6 Alkoxysulfinyl, C 1-6 Alkoxysulfonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulfinyl, heteroarylsulfinyl, arylsulfonyl, or heteroarylsulfonyl optionally substituted on any aromatic moiety, C 1-6Alkylcarbonylamino, C 1-6 Alkoxycarbonylamino, C 1-6 Alkyl-thiocarbonyl, C 1-6 Alkoxy-thiocarbonyl, C 1-6 Alkyl-thiocarbonyloxy, 1-mercaptoC 2-7 alkyl, formyl, or any amino moiety optionally containing one or two C 1-6 Alkyl group, or C 1-6 Alkylsulfinylamino, C 1-6 Alkyl sulfonyl amino, C 1-6 Alkoxysul Finylamino or C 1-6 substituted with alkoxysulfonylamino, or C 1-6 alkylcarbonyl, aminosulfinyl, aminosulfonyl or aminocarbonyl substituted with ethylenyl termini by nitro or cyano, or -C(C 1-6 alkyl)NOH or -C(C 1-6 alkyl)NNH; or one or two C 1-6 optionally substituted with alkyl, or C 2-7 amino optionally substituted with alkanoyl; one of R and R is hydrogen or C 1-4 alkyl, and the other is C 1-4 Alkyl, CF3 or CH2X a are fluoro, chloro, bromo, iodo, C 1-4 Alkoxy, hydroxy, C 1-4 Alkylcarbonyloxy, -SC 1-4 Alkyl, nitro, optionally one or two C 1-4 Amino, cyano, or C substituted with alkyl groups 1-4 or R3 and R4 together are C 1-4 C optionally substituted with alkyl 2-5 Polymethylene; R5 is C 1-6 Alkylcarbonyloxy, benzoyloxy, ONO2, benzyloxy, phenyloxy, or C 1-6alkoxy, and R6 and R9 are hydrogen, or R5 is hydroxy, and R6 is hydrogen or C 1-2 alkyl, and R9 is hydrogen; R7 is heteroaryl or phenyl, both of which are independently and optionally substituted one or more times with groups or atoms selected from chloro, fluoro, bromo, iodo, nitro, amino, where amino is C 1-4 Alkyl, cyano, azido, C 1-4 optionally substituted once or twice with alkoxy, trifluoromethoxy, and trifluoromethyl; R8 is hydrogen, C 1-6 Alkyl, OR 11 or NHCOR 10 where R 11 is hydrogen, C 1-6 Alkyl, formyl, C 1-6 Alkanoyl, aroyl or aryl-C 1-6 alkyl, and R 10 is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, mono or di C 1-6 Alkylamino, Amino-C 1-6 Alkyl, Hydroxy-C 1-6 Alkyl, Halo-C 1-6 Alkyl, C 1-6 Acyloxy-C 1-6 Alkyl, C 1-6 Alkoxycarbonyl-C 1-6 -alkyl, aryl, or heteroaryl; the R8-N-CO-R7 group is cis to the R5 group; and X is oxygen or NR 12 where R 12 is hydrogen or C 1-6 is alkyl; Formula II [ka] During the ceremony, Q is O or the formula =NHOR 43 where R 43 teeth, (i) H, C1-4 fluoroalkyl, or optionally substituted C 1-4 alkyl, or (ii)-A 300 -R 300 wherein A 300 is a direct bond, -C(O)O*-, -C(R3)(R4)O*-, -C(O)OC(R3)(R4)O*- or -C(R3)(R4)OC(O)O*-, where the atom marked with * is 300 R3 and R4 are independently selected from H, Fluoro, and C. 1-4 Alkyl, or C 1-4 fluoroalkyl, or R3 and R4 together with the atom to which they are attached form a cyclopropyl group, and R 300 is selected from the group [1], [2], [2A], [3], [4], [5] or [6]; R2 is H, A is a direct bond, -C(O)O*-, -C(R3)(R4)O*-, -C(O)OC(R3)(R4)O*-, or -C(R3)(R4)OC(O)O*-, where the atom marked with * is directly connected to R1, and R3 and R4 are independently H, fluoro, C 1-4 Alkyl, or C 1-4 fluoroalkyl, or R3 and R4 together with the atom to which they are attached form a cyclopropyl group; R1 is selected from the group [1], [2], [2A], [3], [4], [5] and [6], and atoms marked with ** are directly connected to A; [ka] R5 and R6 are independently H, C 1-4 Alkyl, C 1-4 fluoroalkyl, and benzyl; R7 is independently H, C 1-4 Alkyl, and C 1-4 fluoroalkyl; The R8 is (i) H, C 1-4 Alkyl or C 1-4 fluoroalkyl, or (ii) the side chain of a natural or unnatural alpha-amino acid, or a peptidomimetic or other peptide described herein, or (iii) biotin or chemically linked to biotin; R9 is H, -N(R 11 )(R 12 ), or -N + (R 11 )(R 12 )(R 13 )X - , or -N(R 11 )C(O)R 14 is selected from In the formula, R 11 , R 12 , and R 13 are independently H, C 1-4 Alkyl, or C 1-4 fluoroalkyl; R 14 is H, C 1-4 Alkyl, or C 1-4 is a fluoroalkyl; R 15 independently, C 1-4 Alkyl and C 1-4 fluoroalkyl, and X - is a pharmaceutically acceptable anion.

[0058] The term "comprising," which is synonymous with "comprising," "containing," or "characterized by," is inclusive and open-ended and does not exclude additional, unrecited elements or ingredients from a pharmaceutical product (or, in the case of a method, step). The phrase "consisting of" excludes all elements, steps, or ingredients not specified in the pharmaceutical product (or, in the case of a method, step). The phrase "consisting essentially of" refers to the specified substances and those that do not materially affect the basic and novel characteristics of the pharmaceutical product (or, in the case of a method, step). The basic and novel characteristics of the invention are described throughout this specification and include the ability of the pharmaceutical products and methods of the invention to block or modulate connexin gap junction hemichannels, and in some cases, preserve, protect, and restore or restore retinal structure, preserve, protect, and restore or restore choroidal structure, preserve, protect, and restore or restore retinal function, and preserve, protect, and restore or restore choroidal function. Significant variations in the basic and novel characteristics of the invention, including the pharmaceuticals and methods described herein, include undesirable or clinically undesirable, harmful, inconvenient, or adverse diminution of hemichannel modulation and / or preserving, protecting, and restoring or restoring retinal structure, preserving, protecting, and restoring or restoring choroidal structure, preserving, protecting, and restoring or restoring retinal function, or preserving, protecting, and restoring or restoring choroidal function. In one embodiment, the pharmaceutical comprises, consists essentially of, or consists of a connexin 43 hemichannel blocker, e.g., a small molecule connexin 43 hemichannel blocker.

[0059] In another aspect, the invention provides the use of a hemichannel blocker in the manufacture of a medicament (or a package or kit containing one or more medicaments and / or a container with or without instructions for use) for hemichannel modulation and treatment of any of the diseases, disorders, and / or conditions described or referred to herein. In one aspect, for example, the invention provides the use of a small molecule connexin hemichannel blocker, including Xiflam and / or an analog or prodrug thereof. In one embodiment, the medicament comprises, consists essentially of, or consists of a connexin 43 hemichannel blocker, such as a small molecule connexin 43 hemichannel blocker. In one embodiment, the hemichannel blocker composition useful in the invention may include a pharmaceutically acceptable carrier and may be formulated as a pill, solution, microsphere, liposome, nanoparticle, implant (including, e.g., peritoneal, subcutaneous, and intraocular implants, as well as sustained- or controlled-release implants), matrix, or hydrogel formulation, or may be provided in lyophilized form.

[0060] The hemichannel modulated for the purposes described herein can be any connexin of interest for that purpose. For example, the hemichannel modulated for the purposes described herein can be a connexin hemichannel expressed in the retina, blood vessels, and / or blood vessel walls. In one embodiment, the hemichannel blocker blocks connexin hemichannels in blood vessels. In another embodiment, the hemichannel blocker blocks connexin hemichannels in microvessels. In another embodiment, the hemichannel blocker blocks connexin hemichannels in capillaries. In another embodiment, the hemichannel blocker blocks endothelial connexin hemichannels.

[0061] In various embodiments, illustratively, the modulated hemichannels include one or more of connexin 36 (Cx36), connexin 37 (Cx37), connexin 40 (Cx40), connexin 43 (Cx43), connexin 45 (Cx45), connexin 57 (Cx57), connexin 59 (Cx59), and / or connexin 62 (Cx62).

[0062] In one embodiment, particularly as it relates to the retina, the hemichannels that are modulated include one or more of the Cx36, Cx37, Cx40, Cx43, Cx45, or Cx57 proteins. Targeted hemichannel connexins include select hemichannel connexins in blood vessels. These include one or more of connexins (e.g., Cx37, Cx40, or Cx43) and hemichannels in astrocytes (e.g., Cx43), amacrine cells (e.g., Cx36, Cx45), bipolar cells (e.g., Cx36, Cx45), outer and inner plexiform layers, ganglion cell layer (e.g., Cx36, Cx45), cone photoreceptors and retinal endothelial cells, and other retinal neurons, for example. In some embodiments, Cx36 hemichannels and Cx43 hemichannels are targeted. In one particular embodiment, the hemichannel and / or modulated hemichannel comprises Cx43. In one embodiment, connexin-containing hemichannels (e.g., Cx43) in cells of the outer plexiform layer are targeted, in which case the method can halt and reverse OPL thinning and restore the OPL.

[0063] In other embodiments, particularly relating to choroidal or retinal blood vessels, the modulated hemichannels may selectively comprise one or more of Cx37, Cx40, or Cx43 proteins. In one specific embodiment, the hemichannel and / or modulated hemichannel comprises Cx43. In one embodiment, vascular connexin-containing hemichannels are targeted in cells of the outer choroid, also known as Haller's layer, which is composed of large, non-fenestrated blood vessels. In another embodiment, vascular and endothelial connexin-containing hemichannels are targeted in cells of the inner choroid, also known as Sattler's layer, which is composed of very small blood vessels. In another embodiment, connexin-containing hemichannels are targeted in cells of the outer and inner choroid. In another embodiment, connexin-containing hemichannels are targeted in capillaries of the choriocapillaris. In one embodiment, the hemichannel vascular connexins targeted in the methods of the present invention include hemichannel connexins in pericytes and connexins in vascular smooth muscle cells and endothelial cells. In another embodiment, the hemichannel vascular connexins targeted in the methods of the present invention include hemichannels in pericytes and connexins in endothelial cells, e.g., microcapillaries. Cx43 hemichannels are a preferred target of the present invention.

[0064] Another embodiment of this aspect of the invention provides a pharmaceutical pack comprising a small molecule or other hemichannel blocker, hi one embodiment, the hemichannel blocker is Xiflam (tonabersat).

[0065] In another embodiment, the hemichannel blocker comprises, consists essentially of, or consists of Peptide5, GAP9, GAP19, GAP26, GAP27, or an alpha-connexin carboxy-terminal (ACT) peptide, e.g., ACT-1, or other active anti-hemichannel peptidomimetic.

[0066] The activity of hemichannel blockers may be evaluated using specific biological assays. The effects of known or potential hemichannel blockers on molecular movement can be identified, assessed, or screened using the methods described in the Examples below, or other art-known or equivalent methods for determining the passage of compounds through connexin hemichannels. Various methods are known in the art, including dye transfer experiments, such as the transfer of molecules labeled with detectable markers, and membrane translocation of small fluorescent permeable tracers, which are widely used to test the functional status of hemichannels. Various embodiments of this aspect of the invention are described herein, including methods for use in identifying or assessing the ability of a compound to block a hemichannel, the methods comprising: (a) bringing together a test sample and a test system, the test sample comprising one or more test compounds, and the test system comprising a system for assessing hemichannel blockade, the system being capable of assessing hemichannel blockade, e.g., in response to the introduction of hypoxia or ischemia into the system, in response to inflammatory mediators, or in response to other compounds or compounds that induce hemichannel opening; is an event, e.g., a drop of Ca outside a cell. 2+ and (b) determining, for example, the presence or amount of an increased dye or labeled metabolite in the system. Positive and / or negative controls may also be used. Optionally, a predetermined amount of a hemichannel blocker (e.g., Xiflam) may be added to the test system. Other methods useful for assessing the activity of hemichannel blockers include electrophysiological techniques and channel conductance blockade techniques, all of which are known in the art, that measure a decrease in cytoplasmic swelling or cell edema and a decrease in potassium extrusion from cells.

[0067] In one embodiment, a method for identifying, measuring, or evaluating the activity of a compound useful for restoring or restoring retinal function is provided, including a test using ARPE-19 cells. See Dunn KC, et al., ARPE-19, a human retinal pigment epithelial cell line with differentiated properties. Exp Eye Res. 1996 Feb; 62(2):155-69. Methods in the art for identifying, measuring, or evaluating the activity of a compound useful for restoring or restoring choroidal structure and function may be used. For example, choroidal thickness can be measured using ultrasonography, magnetic resonance imaging (MRI), and enhanced depth imaging optical coherence tomography (EDI-OCT). EDI-OCT is a non-invasive modality that allows cross-sectional imaging of the retina and choroid, and can be used to measure choroidal thickness with acceptable reproducibility and sensitivity. Choroidal thickness has been shown to positively correlate with retinal function, with thicker choroids being associated with better retinal function, as measured, for example, by multifocal electroretinogram (mfERG). Other retinal-choroidal anatomical assessment methods, including swept-source optical computed tomography (SS-OCT), can be used to identify, measure, or evaluate the activity of compounds useful in restoring or restoring choroidal function. [Brief explanation of the drawings]

[0068] [Figure 1A] Figure 1 shows raw ECG waveforms from vehicle- or drug-treated animals (A). Effects of vehicle and a hemichannel modulator (tonabersat) on the amplitude of the mixed a- and b-waves of the ERG using tonabersat at 0.26 mg / kg (B and E), 0.8 mg / kg (C and F), and 2.4 mg / kg (D and G). Vehicle data shown are from 2 weeks after injury. There was no recovery of ERG function in these animals. Statistical analysis was performed using two-way ANOVA with Bonferroni post-hoc tests. Significant values ​​are indicated with asterisks: *p<0.05, **p<0.01, ***p<0.001. [Figure 1BE] Same as above. [Figure 1CF] Same as above. [Figure 1DG] Same as above.

[0069] [Figure 2A-B] Figure 2 shows the effects of vehicle and 2.4 mg / kg of a hemichannel modulator (tonabersat) on the amplitude of the mixed a-wave (A) and b-wave (B) in ERGs from light-damaged rats 3 months after treatment. Analysis of rod PIII (C) and PII (D) shows that untreated animals had significantly reduced amplitude compared to pre-light-damage levels. Treated animals maintained retinal function, matching rod PII controls and only slightly lower than rod PIII controls. All average results are expressed as mean ± SEM. Statistical analysis was performed using two-way ANOVA and Bonferroni post-hoc tests for a-wave and b-wave values. Statistical analysis of rod PII and PIII was performed using unpaired t-tests with Welch's correction. Significant values ​​are indicated with an asterisk: ***p<0.001. LD=light damage. [Figure 2C-D] Same as above.

[0070] [Figure 3A-C]Figure 3 shows the effect of oral delivery of a hemichannel modulator (tonabelsat) on retinal and choroidal thickness in light-damaged rats. Fundus and optical coherence tomography (OCT) images are shown for a normal Sprague Dawley (SD) rat (A), an animal treated with 2.4 mg / kg of tonabelsat 2 weeks after light injury (B), and a vehicle-treated light-damaged rat (C). Green lines in the fundus images represent the scan locations for adjacent cross-sectional OCT images. Colored lines on the OCT images highlight the inner limiting membrane (cyanine), OPL (orange), ONL (orange to yellow), and choroid (green to red). Quantification shows that both the ONL and choroid thinned by 2 weeks after light injury in vehicle-treated animals compared to normal (before light exposure). For each of the three tonabersat doses used, treated animals showed no thinning in the ONL or choroid at any of the analyzed time points: 24 hours, 1 week, and 2 weeks after light injury (columns D-F). There was some thinning at the lowest and middle doses, but it was not significant. **=p<0.01; ***=p<0.001. Scale bar=100 μm [Figure 3D] Same as above. [Figure 3E] Same as above. [Figure 3F] Same as above.

[0071] [Figure 4A-B]Figure 4 shows the effects of vehicle (A) or treatment with a hemichannel modulator (tonabersat, 2.4 mg / kg) (B) 3 months after light injury. Representative OCT images show significant thinning in vehicle-treated animals, with thinning particularly evident in the INL, ONL, and choroid. Colored lines on the OCT images highlight the inner limiting membrane (cyanine), INL (orange to yellow), ONL (yellow to red), choroid (red to purple), and sclera (purple to green). INL, ONL, and choroid thickness measurements are shown in C–E for pre-injury retinas, vehicle-treated 3 months after LD, and tonabelsat-treated 3 months after LD. Data are expressed as mean ± SEM. Significant values ​​compared to the light-injured vehicle (peanut butter) group are indicated with an asterisk: *p<0.05, **p<0.01, ***p<0.001. LD = light damage. Scale bar = 100 μm. [Figure 4C-E] Same as above.

[0072] [Figure 5] Figure 5 shows immunohistochemical analysis of the effects of three concentrations of an orally delivered hemichannel modulator (tonabersat) on light-damaged rats. Orally treated rats had lower connexin 43 immunoreactivity in the retina at all three dose levels (B–D) compared with the vehicle group (A). Iba-1 immunolabeled cells showed less activation (sprouting) in the IPL of the retinas of tonabersat-treated rats at all three doses (F–H) compared with vehicle-treated rats (E). However, a slight increase in Iba-1 reactivity was evident at the lowest oral dose of 0.26 mg / kg. GFAP immunoreactivity was not increased in the retinas of 0.8 mg / ml (K) and 2.4 mg / kg (L) compared with vehicle rats (I). At the lowest oral dose of 0.26 mg / kg, GFAP labeling increased slightly, but expression was still lower than that of vehicle alone (J). Abbreviations: CGL: ganglion cell layer, inner plexiform layer of the IPL. Scale bar: 50 μm.

[0073] [Figure 6]Figure 6 shows quantification of GFAP immunoreactive areas (A), connexin 43 expression (B), and mean numbers of Iba-1-activated cells (C) in animals treated with each of three oral tonaversat dose levels compared to vehicle alone in light-damaged rats. Analysis revealed significantly lower upregulation of GFAP and connexin 43 in all three tonaversat-treated groups compared to vehicle controls (p<0.001) (A-B). Quantification of Iba-1-positive cells revealed significantly reduced numbers of activated microglia in all three tonaversat-treated groups compared to vehicle (p<0.001) (C). Statistical analysis was performed using one-way ANOVA followed by Tukey's multiple comparison test. Values ​​significant compared to untreated results are indicated with an asterisk: ***p<0.001.

[0074] [Figure 7A-C] Figure 7 shows representative OCT images from a hyperglycemic rat, showing an average of 5–8 hyperreflective spots per eye (based on seven evenly spaced OCT scans across the retina, thus resulting in an underestimation of the entire eye), but none in a normal SD rat (A). The hyperreflective spots appear to represent microaneurysms (<20 μm in diameter; arrows in B0) and giant aneurysms (140–160 μm; arrows in C), which were particularly located in the INS and ONL. Colored lines on the OCT image highlight the INL (orange to yellow), ONL (yellow to red), and choroid (purple to cyan). Evans blue dye perfusion confirmed vascular leakage at the sites of aneurysms mapped using OCT. The green lines in the fundus image (D) indicate where the OCT scan (E) was taken. The hyperreflective spots (arrows) represent microaneurysms. Rats were injected with Evans blue, and then the retinas were removed and imaged in areas where vascular leakage was evident (F). While leakage was not associated with all microaneurysms, vascular leakage was consistently observed in four hyperglycemic rats with microaneurysms. Scale bar = 100 μm. [Figure 7D-F] Same as above.

[0075] [Figure 8A-B] Figure 8 shows ERG analysis of retinal function in 5-week-old hyperglycemic strains compared with normal SD rats from which they were derived. Representative ERG mixed a- and b-waves are shown in A and B. The mean mixed a-wave amplitude was significantly reduced in hyperglycemic rats compared with normal SD rats. The mean mixed b-wave amplitude was also significantly reduced in hyperglycemic rats compared with normal SD rats. Decomposition analysis showed that the amplitudes of rod PIII (C), PII (D), and cone PII (E) responses were significantly reduced in hyperglycemic rats and compared with the OP control group. Statistical analysis was performed using one-way ANOVA followed by Tukey's multiple comparison test. Significant values ​​compared with normal SD are indicated with asterisks: **p<0.01; ***p<0.001. OP = pulsating potential. [Figure 8C-F] Same as above.

[0076] [Figure 9A-B] Figure 9 shows OCT and ERG analysis of retinal structure and function in hyperglycemic rats treated once daily for 14 days (weeks 5–7) at week 8 (the lowest dose used, 0.28 mg / kg) compared with vehicle-treated animals. (A) shows a hyperreflective spot that is nearly invisible after treatment (B). ERGs were significantly restored in treated hyperglycemic rats compared with vehicle-treated rats, while untreated rats further deteriorated from week 5 to week 8. In treated animals, the mixed a-wave was significantly higher at week 8 compared with vehicle-treated animals (C). Similarly, the mixed b-wave was significantly restored in tonabersat-treated animals at all intensities compared with vehicle controls (D). Further analysis revealed that treated hyperglycemic rats had significant recovery in rod PIII (E), PII (F), cone PII (G), and total OP (H) amplitudes. Statistical analysis was performed using one-way ANOVA followed by Tukey's multiple comparison test. Values ​​significant compared to vehicle treatment are indicated with an asterisk: **p<0.01; ***p<0.001. OP=pulsatile potential. Scale bar=100 μm [Figure 9C-D] Same as above. [Figure 9E-H] Same as above.

[0077] [Figure 10A-F] Figure 10 shows immunohistochemical labeling in tonabelsat- and vehicle-treated 8-week-old hyperglycemic rats. GFAP labeling was intense in the CGL, where astrocytes were present in the area surrounding microaneurysms in the hyperglycemic rat retina, extending from the nerve fiber layer to the ONL, suggesting Müller cell activation (A). In hyperglycemic retinas in the IPL, abnormally high Iba-1 labeling was present (B), where cells with swollen cell bodies and numerous elongated branches were present. Connexin 43 labeling was abnormally high in the GCL of untreated animals (C). Hyperglycemic rats given tonabelsat daily for 14 days had reduced inflammation, as evidenced by labeling for all three markers (D–F). Quantification of the results in G-I shows that all three markers, GFAP, connexin 43, and Iba-1, were significantly higher in vehicle-treated rats compared to uninjured control retinas, and tonabersat treatment significantly reduced labeling at 8 weeks, significantly lower than retinal levels in untreated rats. Statistical analysis was performed using one-way ANOVA followed by Tukey's multiple comparison test. Values ​​significant compared to results from the untreated group are indicated with an asterisk: ***p<0.001. Scale bar = 100 μm. [Figure 10G-I] Same as above. DETAILED DESCRIPTION OF THE INVENTION

[0078] Increased connexin 43 hemichannel opening is associated with inflammasome pathway activation and inflammation in various pathologies, including ocular disorders. Using a light-damaged retinal animal model of dry AMD and a spontaneous rat model of DR, we discovered the utility of clinically safe doses of orally delivered small molecule connexin hemichannel blockers, such as Xiflam, in restoring and restoring retinal function and morphology, as well as choroidal function and structure. Clinical parameters (fundus angiography, optical coherence tomography (OCT), and electroretinogram) and inflammatory markers (Iba-1 microglial marker, astrocytic marker glial fibrillary acidic protein, and immunohistochemistry for connexin 43 protein expression) were assessed, demonstrating that hemichannel blocker treatment resulted in the preservation of retinal photoreceptor function in dry AMD models up to 3 months after light injury. In a DR model, clinical signs, including the presence of aneurysms confirmed using Evans blue dye perfusion, were reduced after two weeks of once-daily treatment with tonabersat. Inflammation was also reduced, and retinal function was restored. We have discovered that the use of hemichannel blockers can not only improve but also reverse anatomical and functional outcomes in chronic retinal disease.

[0079] Surprisingly, a single dose of orally administered hemichannel blockers was found to be neuroprotective over an evaluation period of up to three months after acute light injury. Hemichannel blocker treatment was found to significantly preserve retinal function, particularly the function of inner retinal photoreceptors and bipolar cells. Furthermore, the increase in rhythmic wavelets identified using each of the three hemichannel blocker doses tested indicates a preservation effect on inner retinal cells despite light injury. Improvements in PIII and PII responses in electroretinograms (ERGs) also indicate specific preservation of the phototransduction pathway and post-photoreceptor neuronal responses. The study described in Example 2 also demonstrated that hemichannel blockers can be used to preserve retinal layer structure as measured by optical coherence tomography (OCT). For further details of these findings, see Example 2.

[0080] Furthermore, hemichannel blockers, such as the oral blocker Xiflam, were found to be effective in abolishing the signs of DR secondary to spontaneous and chronic systemic hyperglycemia in a diabetic SD rat model, as shown in Example 3. Signs of retinal microaneurysms and giant aneurysms, with associated impact on visual retinal function, were found in phenotypic models of diabetes and DR.

[0081] The use of an oral hemichannel blocker, in this case Xiflam, demonstrated regression of micro- and giant aneurysms and significant restoration of retinal function as measured by ERG compared with placebo controls. Results from these distinct models are consistent with other chronic ocular inflammatory diseases. This has implications for diseases, particularly those involving the inflammasome pathway. Hemichannel blockade in the macular degeneration and diabetic retinopathy models described in this patent not only reduced inflammation but also, surprisingly, rescued and restored retinal structure and function, and importantly, choroidal structure.

[0082] This application relates to the surprising discovery that modulation of hemichannel opening has direct, long-term effects on retinal structure and function, as well as the maintenance and restoration of choroidal structure. See Examples 1-3 below. These discoveries have important implications for the treatment of various diseases, disorders, and conditions characterized in whole or in part by loss of retinal structure and / or function, including diabetic retinopathy, for which there is no known cure.

[0083] It has also been discovered that hemichannel blockers, including, for example, connexin 43 hemichannel blockers, can be used to preserve the choroid, and thus can be used in methods for preserving choroidal function in disease states.

[0084] definition As used herein, the term "about" of a value or parameter refers to the art-understood meaning and includes embodiments that are directed to the value or parameter itself. For example, a statement referring to "about X" includes the statement "X." For example, the term "about 5 mg" of a dose weight value refers to + / - 0.5 of the weight value.

[0085] A "small molecule" is defined herein as having a molecular weight of less than about 600-900 daltons and is generally an organic compound. A small molecule can be the active agent of a hemichannel blocker prodrug. In one embodiment, the small molecule is less than 600 daltons. In another embodiment, the small molecule is less than 900 daltons.

[0086] As used herein, "treatment" (and grammatical variations such as "treat" or "treating") refers to a clinical intervention that alters the natural course of the individual, tissue, or cell being treated, and can be performed either for prophylactic purposes or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, prevention of the onset or recurrence of a disease, disorder, or condition, alleviation of signs or symptoms, diminishment of any direct or indirect pathological consequences of a disease, slowing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. In some embodiments, the compounds, methods, and compositions of the invention can be used to delay the onset of a disease, disorder, or condition or slow the progression of a disease, disorder, or condition. The term does not necessarily imply that a subject is treated until total recovery. Thus, "treatment" includes reducing, alleviating, or ameliorating the symptoms or severity of a particular disease, disorder, or condition, or preventing or otherwise reducing the risk of developing a particular disease, disorder, or condition. It may also include maintaining or promoting complete or partial remission of a condition.

[0087] As used herein, "treatment" includes maintaining and / or restoring retinal structure, maintaining and / or restoring retinal function, maintaining and / or restoring choroidal structure, and / or maintaining and / or restoring choroidal function in a subject after administration of a hemichannel blocker. A preferred hemichannel blocker is Xiflam. A preferred route of administration is oral.

[0088] The term "treating" a disease, condition, or disorder, etc., includes preventing, slowing, reducing, diminishing, and especially halting and reversing the disorder, disease, and / or condition, and / or improving, restoring, or recovering or normalizing the structure and / or function of the retina. In particular, for example, in halting or reversing a disorder, disease, or condition, or in restoring retinal function and / or structure, or choroidal function and / or structure, one or more or all of the symptoms of the disorder, disease, or condition are reversed or substantially eliminated, the ONL of the retina is restored, restored, and / or normalized, retinal ERG function, inner retinal function, retinal photoreceptor function (especially rod photoreceptor function), and / or retinal PIII and PII rod responses are restored, restored, and / or normalized, and the choriocapillaris of the choroid are restored, restored, and / or normalized.

[0089] In other embodiments, the outer and inner nuclear layers of the retina are protected using the compounds and methods described herein as shown in the Examples, which are important in chronic retinal diseases, including age-related macular degeneration, and further find utility in the protective effects of the present invention.

[0090] The term "preventing" means to prevent, or ameliorate, or control in whole or in part.

[0091] As used herein, "effective amount" refers to an amount effective at a dosage and for a period of time necessary to achieve a desired therapeutic or preventative result. For example, but not limited to, "effective amount" can refer to the amount of a compound or composition disclosed herein that can treat signs and / or symptoms of a disease, disorder, or condition involving dysfunctional retinal and / or choroidal structure and / or function, or can refer to the amount of a hemichannel compound or hemichannel composition that can beneficially regulate and restore dysfunctional retinal and / or choroidal structure and / or function.

[0092] As used herein, the "therapeutically effective amount" of a substance / molecule, agonist, or antagonist of the present invention can vary depending on factors such as the disease state, the individual's age, sex, and weight, and the ability of the substance / molecule, agonist, or antagonist to induce a desired response in the individual. A therapeutically effective amount is also preferably an amount in which any toxic or harmful effects of the substance / molecule, agonist, or antagonist can be outweighed by the therapeutically beneficial effects. A therapeutically effective amount of a hemichannel blocker beneficially maintains or improves the structure and / or function of the retina and / or the structure and / or function of the choroid in a subject.

[0093] As used herein, a "prophylactically effective amount" refers to an amount effective to achieve a desired prophylactic result, typically at a dosage and for a period of time necessary to maintain restored or recovered retinal and / or choroidal function and / or structure. Typically, but not necessarily, a prophylactically effective amount is less than a therapeutically effective amount.

[0094] The term "pharmaceutical formulation" refers to a preparation that is in a form that allows the biological activity of the active ingredient, e.g., a hemichannel blocker, contained therein to be effective, and that does not contain additional ingredients that are unacceptably toxic to the subject to which the formulation is administered.

[0095] As used herein, "pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical formulation other than the active ingredient that can be safely administered to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, and preservatives.

[0096] As used herein, terms such as "subject," including "individual" and "patient," refer to All of these may be used interchangeably herein and refer to any mammal, including humans, livestock and farm animals, as well as zoo animals, wildlife park animals, sport animals, or pet animals, such as dogs, horses, cats, sheep, pigs, cows, etc. Preferred mammals are humans, including adults, children, and the elderly. Preferred sport animals are horses and dogs. Preferred pet animals are dogs and cats. In certain embodiments, the subject, individual, or patient is a human.

[0097] As used herein, the term "hemichannel" refers to a part of a gap junction (two hemichannels or connexons connect across the intercellular space between adjacent cells to form a gap junction) and is composed of many connexin proteins, typically homo- or hetero-conjugated, i.e., homohexamers or heterohexamers of connexin proteins, that form the pore for the gap junction between the cytoplasm of two adjacent cells. A hemichannel is provided by a cell on one side of the junction, and two hemichannels from opposing cells usually join together to form a complete intercellular hemichannel. However, in some cells, and under some circumstances, the hemichannel itself is active as a conduit between the cytoplasm and the extracellular space, allowing the transport of ions and small molecules.

[0098] Compounds of Formula I, such as Xiflam, and / or analogs or prodrugs of any of the foregoing compounds, can modulate the function and / or activity of hemichannels, preferably hemichannels comprising any type of connexin protein. Therefore, unless the context requires otherwise, reference to a "hemichannel" is intended to be taken broadly to include hemichannels comprising, consisting essentially of, or consisting of any one or more of various connexin proteins. However, by way of example, a hemichannel may comprise one or more of any connexin, including those specifically mentioned above. In one embodiment, a hemichannel consists of one of the aforementioned connexins. In one embodiment, a hemichannel comprises one or more of connexins 36, 37, 40, 43, 45, and 57. In one embodiment, a hemichannel consists of one of connexins 37, 40, or 43. In one embodiment, a hemichannel is a connexin 43 hemichannel. In one embodiment, a hemichannel is a retinal hemichannel. In one embodiment, a hemichannel is a choroidal hemichannel. In one embodiment, the hemichannel is a vascular hemichannel. In one embodiment, the hemichannel is a connexin hemichannel present in vascular endothelial cells. In one specific embodiment, the hemichannel comprises one or more of connexin 30, 37, and connexin 43. In one specific embodiment, the hemichannel comprises connexin 30. In one specific embodiment, the hemichannel comprises connexin 37. In one specific embodiment, the hemichannel comprises connexin 43. In one embodiment, the hemichannel comprises one or more connexins excluding connexin 26. In one embodiment, the composition may include or exclude hemichannel blockers of any connexin, including those described above.

[0099] Hemichannels can be present in any type of cell. Thus, unless the context requires otherwise, reference to a "hemichannel" shall be taken to include a reference to a hemichannel, or to a hemichannel present in any cell type. In one embodiment of the present invention, the hemichannel is present in a cell, an organ, or a cancer or tumor. In one embodiment, the hemichannel is a vascular hemichannel. In one embodiment, the hemichannel is a connexin hemichannel present in vascular endothelial cells and / or vascular smooth muscle cells, or in the retina and / or choroid, or in the choroidal vasculature.

[0100] As used herein, "modulating a hemichannel" refers to modulating one or more functions and / or activities of a hemichannel, typically modulating the flow of molecules between cells through the hemichannel. Such functions and activities include, for example, the flow of molecules from the extracellular space or environment through the hemichannel into the cell, and / or the flow of molecules from the intracellular space or environment through the hemichannel to the extracellular space or environment. Compounds useful for modulating hemichannels are sometimes referred to as "hemichannel modulators." All aspects of the inventions and methods described herein can be achieved by modulating hemichannels.

[0101] Modulation of hemichannel function may be achieved by any means. However, by way of example only, modulation may be achieved by one or more of inducing or promoting hemichannel closure; preventing, blocking, inhibiting, or reducing hemichannel opening; and triggering, inducing, or promoting cellular internalization of hemichannels and / or gap junctions. For example, the use of terms such as "blocking," "inhibiting," "preventing," "reducing," and "antagonizing" should not be taken to imply complete blockage, inhibition, prevention, or antagonism, but rather should be taken to include partial blockage, inhibition, prevention, or antagonism to at least reduce hemichannel function or activity and / or hemichannel activity. Similarly, "inducing" or "promoting" should not be taken to imply complete internalization of a hemichannel (or group of hemichannels), but should be taken to include partial internalization to at least reduce hemichannel function or activity.

[0102] As used herein, the terms "anti-hemichannel compound" and "hemichannel blocker" refer to compounds that interfere with the passage of molecules through connexin hemichannels. Anti-hemichannel compounds or hemichannel blockers may block or reduce the opening of hemichannels, block or reduce the release of molecules through the hemichannel into the extracellular space, and / or block or reduce the entry of molecules through the hemichannel into the intracellular space. Anti-hemichannel compounds and hemichannel blockers include compounds that completely or partially block hemichannel leakage or the passage of molecules from or to the extracellular space. Anti-hemichannel compounds and hemichannel blockers also include compounds that decrease the open probability of a hemichannel. Open probability is a measure of the proportion of time a channel remains open versus closed (Goldberg GS, et al., Selective permeability of gap junction channels (Reviewed in Biochimica et Biophysica Acta 1662 (2004) 96-101). Anti-hemichannel compounds and hemichannel blockers include hemichannel modulators. Anti-hemichannel compounds and hemichannel blockers may directly or indirectly interfere with the passage of molecules through connexin hemichannels. All aspects of the inventions and methods described herein can be achieved, for example, by blocking hemichannels or reducing the open probability of hemichannels as described herein. In one embodiment, the connexin hemichannel is a connexin 43 hemichannel and / or other vascular connexin hemichannel.

[0103] As used herein, the terms "restore or restore retinal structure" and "restore or restore retinal structure," "restoring and / or restoring retinal structure," and the like refer to improving the integrity of retinal structure, including, for example, restoration of retinal pigment epithelium, restoration of retinal vascular endothelium, and / or restoration of normal retinal layer structure. The term "restore or restore retinal structure" also refers to the reduction or elimination of microaneurysms and / or macroaneurysms (see FIG. 9B). In some embodiments of the present invention, retinal structure is restored and returned to a normal or pre-disease state. In some embodiments of the present invention, the retinal pigment epithelium, retinal vascular endothelium, and / or macroaneurysms are reduced or eliminated. Alternatively, the retinal layer structure is restored and returned to a normal or pre-disease state.

[0104] The terms "restoring or restoring retinal function," "restoring or restoring retinal function," "restoring retinal function, and / or restoring retinal function," and the like, refer to improving retinal function, including, for example, improving mixed a-wave function (see, e.g., FIG. 9C), improving mixed b-wave function (see, e.g., FIG. 9D), and / or improving PII and PIII rod and cone function (see, e.g., FIG. 9E-G), which may be assessed, for example, by electroretinogram. The term "restoring or restoring retinal function" also refers to improving overall ERG function. See also FIG. 1, which illustrates restoration of ERG function and inner retinal function, and FIG. 2, which illustrates improved photoreceptor function. In some embodiments of the invention, retinal function is restored and returned to a normal or pre-disease state. In some embodiments of the invention, retinal ERG, PII and PIII rod and / or cone function, and the like, are restored and returned to a normal or pre-disease state.

[0105] As used herein, the terms "restoration or restoration of choroidal structure," "restoration or restoration of choroidal structure," "restoring and / or restoring choroidal structure," and the like refer to an improvement in the integrity of the choroidal structure, including restoration of choroidal thickness and / or restoration of the choroidal vascular bed, which may be determined, for example, using OCT angiography or fluorescein angiography. In some embodiments of the present invention, the choroidal structure is restored and returned to a normal or pre-disease state. In some embodiments of the present invention, the choroidal thickness and / or choroidal vascular bed is restored and returned to a normal or pre-disease state.

[0106] As used herein, the terms "restore or restore choroidal function," "restore or restore choroidal function," "restoring choroidal function," and / or "restoring" refer to an improvement in choroidal blood flow, which can be determined, for example, using high-speed OCT angiography. The term "restore or restore choroidal function" also refers to an improvement in choroidal vascular blood flow to the outer retina and an improvement in the regulation of choroidal blood flow. In some embodiments of the present invention, choroidal function is restored and returned to a normal or pre-disease state. In some embodiments of the present invention, choroidal blood flow is restored and returned to a normal or pre-disease state.

[0107] The compounds of the present invention may be used in therapeutic methods for preserving or restoring retinal structure, retinal function, choroidal structure, and / or choroidal function, including in methods for treating diseases, disorders, or conditions characterized, in whole or in part, by pathological abnormalities or otherwise undesirable or undesirable reductions in the integrity of retinal and / or choroidal structure or function. The integrity of the retina and / or choroid is essential for preventing vision loss.

[0108] The terms "peptide," "peptidomimetic," and "mimetic" include synthetically or genetically engineered compounds that may have substantially the same structural and functional characteristics as the protein regions they mimic. In the case of connexin hemichannels, these may, for example, mimic the extracellular loops of a hemichannel connexin.

[0109] This patent describes novel methods for preserving or restoring retinal structure, retinal function, choroidal structure, and / or choroidal function, which can be improved by the methods of the present invention in many diseases, disorders, or conditions, some of which are characterized by chronic retinal dysfunction and / or loss of retinal structure, and / or chronic choreal dysfunction and / or loss of choroidal structure.

[0110] The present invention particularly relates to the treatment of diseases, disorders or conditions characterized in whole or in part by loss of retinal structure, retinal function, choroidal structure, and / or choroidal function, e.g., Xi The present invention provides methods for preserving or restoring retinal structure, retinal function, choroidal structure, and / or choroidal function by administering a hemichannel blocker, such as a compound of Formula I, such as flam, or a compound of Formula II, and / or an analog or prodrug of any of the foregoing compounds.

[0111] In some embodiments, the invention features the use of a compound of Formula I, such as Xiflam, or a compound of Formula II, and / or an analog or prodrug of any of the foregoing compounds, to directly and immediately block Cx43 hemichannels, resulting in the preservation or restoration of retinal structure, function, choroidal structure, and / or function. Some exemplary doses range from about 0.1 to about 5.0 mg / kg, including, for example, 0.2 to 3.0 mg / kg, or 0.2 to 2 mg / kg, and 0.2 to 1.0 mg / kg, or 0.2 to 0.5 mg / kg. Some exemplary daily doses, or other regular doses, range from about 10 to 250 mg per dose, including, for example, about 20 to 25 mg per dose, about 25 to 50 mg per dose, about 50 to 75 mg per dose, about 75 to 100 mg per dose, and about 100 to 250 mg per dose, including doses of 20, 50, 100, and 150 mg per dose.

[0112] Connexins In various embodiments, the modulated hemichannel is any connexin hemichannel, and may include or exclude connexin 26 (Cx26) hemichannels. In specific embodiments, the modulated hemichannel is a connexin 36 (Cx36) hemichannel, a connexin 37 (Cx37) hemichannel, a connexin 40 (Cx40) hemichannel, a connexin 43 (Cx43) hemichannel, a connexin 45 (Cx45) hemichannel, and / or a connexin 57 (Cx57) hemichannel. In one embodiment, the modulated hemichannel comprises one or more of the Cx36, Cx37, Cx40, Cx43, Cx45, and / or Cx57 proteins. In one specific embodiment, the hemichannel and / or modulated hemichannel is a Cx37 and / or Cx40 and / or Cx43 hemichannel. In one particular embodiment, the hemichannel and / or modulated hemichannel is a Cx30 and / or Cx43 and / or Cx45 hemichannel, hi one particular embodiment, the hemichannel and / or modulated hemichannel is a Cx36, Cx37, Cx43, and / or Cx45 hemichannel.

[0113] In some embodiments, the modulated hemichannel may include or exclude any of the aforementioned connexin proteins. In some aspects, the hemichannel blocker is a blocker of Cx43 hemichannel, Cx40 hemichannel, and / or Cx45 hemichannel. In certain preferred embodiments, the hemichannel blocker is a connexin 43 hemichannel blocker. The pharmaceutical compositions of the invention for any of the uses characterized herein may also include a hemichannel blocker that can inhibit or block any of the described connexin hemichannels (including homologous and heterologous hemichannels). In some embodiments, the modulated hemichannel may include or exclude any of the aforementioned connexin hemichannels, or may be a heteromeric hemichannel.

[0114] The hemichannel blocker used in any of the administration, co-administration, compositions, kits, or methods of treatment of the present invention is, in one embodiment, a Cx43 hemichannel blocker. Other embodiments include connexin hemichannels or hemichannels, including Cx45 hemichannel blockers, Cx30 hemichannel blockers, Cx37 hemichannel blockers, Cx40 hemichannel blockers, and those comprising, or consisting essentially of, any other connexin described above or herein. Some embodiments may include or exclude any of the aforementioned connexins or hemichannels, or other connexins or hemichannels described in this patent. Illustratively, in various embodiments, the modulated hemichannels include one or more of connexin 36, connexin 37, connexin 40, connexin 43, connexin 45, connexin 57, connexin 59, and / or connexin 62.

[0115] In one embodiment, particularly with respect to the retina, the modulated hemichannel comprises one or more of the Cx36, Cx37, Cx40, Cx43, Cx45, or Cx57 proteins. Targeted hemichannel connexins include select hemichannel connexins in blood vessels (e.g., Cx37, Cx40, or Cx43) and one or more of the hemichannel connexins in astrocytes (e.g., Cx43), amacrine cells (e.g., Cx36, Cx45), bipolar cells (e.g., Cx36, Cx45), outer and inner plexiform layers, ganglion cell layers (e.g., Cx36, Cx45), cone photoreceptors and retinal endothelial cells, and other retinal neurons, for example. In some embodiments, Cx36 and Cx43 hemichannels are targeted. In one specific embodiment, the hemichannel and / or modulated hemichannel comprises Cx43. In one embodiment, connexin-containing hemichannels (e.g., Cx43) in cells of the outer plexiform layer are targeted, in which case the method of the present invention can halt and reverse the thinning of the OPL and restore the OPL.

[0116] In other embodiments, particularly relating to choroidal or retinal blood vessels, the modulated hemichannels may selectively comprise one or more of Cx37, Cx40, or Cx43 proteins. In one specific embodiment, the hemichannel and / or modulated hemichannel comprises Cx43. In one embodiment, vascular connexin-containing hemichannels are targeted in cells of the outer choroid, also known as Haller's layer, which is composed of large, non-fenestrated blood vessels. In another embodiment, vascular and endothelial connexin-containing hemichannels are targeted in cells of the inner choroid, also known as Sattler's layer, which is composed of very small blood vessels. In another embodiment, connexin-containing hemichannels are targeted in cells of the outer and inner choroid. In another embodiment, connexin-containing hemichannels are targeted in capillaries of the choriocapillaris. In one embodiment, the hemichannel vascular connexins targeted in the methods of the present invention include hemichannel connexins in pericytes and connexins in vascular smooth muscle cells and endothelial cells. In another embodiment, the hemichannel vascular connexins targeted in the methods of the present invention include hemichannels in pericytes and connexins in endothelial cells, e.g., microcapillaries. Cx43 hemichannels are a preferred target of the present invention.

[0117] Small molecule hemichannel blockers Examples of hemichannel blockers include small molecule hemichannel blockers such as Xiflam (tonabersat). The structure of tonabersat (also shown in PubChem, DrugBank, and MedChemExpress) is: [ka]

[0118] Other chemical names for tonabersat are listed in PubChem (N-[(3S,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]-3-chloro-4-fluorobenzamide), DrugBank (N-[(3S,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl]-3-chloro-4-fluorobenzamide), and Chemical Book (N-((3S,4S)-6-acetyl-3-hydroxy-2,2-dimethylchroman-4-yl)-3-chloro-4-fluorobenzamide; or 2H-benzo(B)pyran-3-ol, 6-acetyl-4-(3-chloro-4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-; or N-[(3S,4S)-6-acetyl-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl]-3-chloro-4-fluoro-benzamide).

[0119] In some embodiments, the hemichannel blocker is a small molecule other than Xiflam, e.g., a hemichannel blocker described in Formula I or Formula II of U.S. Patent Application Publication No. 20160177298, filed in the names of Colin Green et al., the disclosure of which is incorporated herein by reference in its entirety as set forth above. Various preferred embodiments include the use of small molecules that block, improve, or otherwise antagonize or inhibit the opening of hemichannels to treat the diseases, disorders, and conditions described or referenced herein. In various embodiments, the small molecule that blocks, improves, or inhibits hemichannel opening is a prodrug of Xiflam or an analog thereof.

[0120] In some embodiments, the invention features the use of small molecule hemichannel blockers, including compounds of Formula I, such as Xiflam, and / or analogs or prodrugs of any of the foregoing compounds that block Cx43 hemichannels, for example, to restore or restore retinal structure, to restore or restore retinal function, and to restore or restore choroidal structure and / or function.

[0121] By way of illustration, the hemichannel blocker Xiflam (tonabersat) may be known by the IUPAC name N-[(3S,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]-3-chloro-4-fluorobenzamide, or (3S-cis)-N-(6-acetyl-3,4-dihydro-3-hydroxy-2,2-(dimethyl-d6)-2H-1-benzopyran-4-yl)-3-chloro-4-fluorobenzamide.

[0122] Another useful compound is boldine, found in Bordeaux wood and tenderloin. It is an aporphine alkaloid found in Lindera aggregata.

[0123] In one embodiment, Xiflam and / or its analogs or prodrugs are selected from the group of compounds having Formula I: [ka] During the ceremony, Y is C-R1; R1 is acetyl; R2 is hydrogen, C 3-8 Cycloalkyl, optionally interrupted by oxygen, or hydroxy, C 1-6 C substituted by alkoxy or substituted aminocarbonyl 1-6 Alkyl, C 1-6 Alkyl carbonyl, C 1-6 Alkoxycarbonyl, C 1-6 Alkylcarbonyloxy, C 1-6alkoxy, nitro, cyano, halo, trifluoromethyl, or CF3S; or a CF3-A- group, where A is -CF2-, -CO-, -CH2-, CH(OH), SO2, SO, CH2-O-, or CONH; or a CF2H-A'- group, where A' is oxygen, sulfur, SO, SO2, CF2, or CFH; trifluoromethoxy, C 1-6 Alkyl sulfinyl, perfluoro C 2-6 Alkylsulfonyl, C 1-6 Alkylsulfonyl, C 1-6 Alkoxysulfinyl, C 1-6 Alkoxysulfonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulfinyl, heteroarylsulfinyl, arylsulfonyl, or heteroarylsulfonyl optionally substituted on any aromatic moiety, C 1-6 Alkylcarbonylamino, C 1-6 Alkoxycarbonylamino, C 1-6 Alkyl-thiocarbonyl, C 1-6 Alkoxy-thiocarbonyl, C 1-6 Alkyl-thiocarbonyloxy, 1-mercaptoC 2-7 alkyl, formyl, or any amino moiety optionally containing one or two C 1-6 Alkyl group, or C 1-6 Alkylsulfinylamino, C 1-6 Alkyl sulfonyl amino, C 1-6 Alkoxysulfinylamino or C 1-6 substituted with alkoxysulfonylamino, or C 1-6 alkylcarbonyl, aminosulfinyl, aminosulfonyl or aminocarbonyl substituted with ethylenyl termini by nitro or cyano, or -C(C 1-6 alkyl)NOH or -C(C 1-6 alkyl)NNH; or one or two C 1-6 optionally substituted with alkyl, or C 2-7amino optionally substituted with alkanoyl; one of R and R is hydrogen or C 1-4 alkyl, and the other is C 1-4 Alkyl, CF3 or CH2X a are fluoro, chloro, bromo, iodo, C 1-4 Alkoxy, hydroxy, C 1-4 Alkylcarbonyloxy, -SC 1-4 Alkyl, nitro, optionally one or two C 1-4 Amino, cyano, or C substituted with alkyl groups 1-4 or R3 and R4 together are C 1-4 C optionally substituted with alkyl 2-5 Polymethylene; R5 is C 1-6 Alkylcarbonyloxy, benzoyloxy, ONO2, benzyloxy, phenyloxy, or C 1-6 and R6 and R9 are hydrogen. or R5 is hydroxy and R6 is hydrogen or C 1-2 alkyl, and R9 is hydrogen; R7 is heteroaryl or phenyl, both of which are independently and optionally substituted one or more times with groups or atoms selected from chloro, fluoro, bromo, iodo, nitro, amino, where amino is C 1-4 Alkyl, cyano, azido, C 1-4 optionally substituted once or twice with alkoxy, trifluoromethoxy, and trifluoromethyl; R8 is hydrogen, C 1-6 Alkyl, OR 11 or NHCOR 10 where R 11 is hydrogen, C 1-6 Alkyl, formyl, C 1-6 Alkanoyl, aroyl or aryl-C 1-6 alkyl, and R 10 is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, mono or di C 1-6Alkylamino, Amino, Amino-C 1-6 Alkyl, Hydroxy-C 1-6 Alkyl, Halo-C 1-6 Alkyl, C 1-6 Acyloxy-C 1-6 Alkyl, C 1-6 Alkoxycarbonyl-C 1-6 -alkyl, aryl, or heteroaryl; the R8-N-CO-R7 group is cis to the R5 group; and X is oxygen or NR 12 where R 12 is hydrogen or C 1-6 It is alkyl.

[0124] In some embodiments, the invention features the use of small molecule hemichannel blockers, including, for example, compounds of formula II and / or analogs or prodrugs of any of the foregoing compounds that block Cx43 hemichannels, for example, to restore or restore retinal structure, to restore or restore retinal function, and to restore or restore choroidal structure and / or function. Formula II [ka] During the ceremony, Q is O or the formula =NHOR 43 where R 43 teeth, (i) H, C 1-4 fluoroalkyl, or optionally substituted C 1-4 alkyl, or (ii)-A 300 -R 300 wherein A 300 is a direct bond, -C(O)O*-, -C(R3)(R4)O*-, -C(O)OC(R3)(R4)O*- or -C(R3)(R4)OC(O)O*-, where the atom marked with * is 300 R3 and R4 are independently selected from H, Fluoro, and C. 1-4 Alkyl, or C 1-4fluoroalkyl, or R3 and R4 together with the atom to which they are attached form a cyclopropyl group, and R 300 is [1], [2], [2A], [3], [4], [5] or [6 ] selected from the group R2 is H, A is a direct bond, -C(O)O*-, -C(R3)(R4)O*-, -C(O)OC(R3)(R4)O*-, or -C(R3)(R4)OC(O)O*-, where the atom marked with * is directly connected to R1, and R3 and R4 are independently H, fluoro, C 1-4 Alkyl, or C 1-4 fluoroalkyl, or R3 and R4 together with the atom to which they are attached form a cyclopropyl group; R1 is selected from the group [1], [2], [2A], [3], [4], [5] and [6], and atoms marked with ** are directly connected to A; [ka] R5 and R6 are independently H, C 1-4 Alkyl, C 1-4 fluoroalkyl, and benzyl; R7 is independently H, C 1-4 Alkyl, and C 1-4 fluoroalkyl; The R8 is (i) H, C 1-4 Alkyl or C 1-4 fluoroalkyl, or (ii) the side chain of a natural or unnatural alpha-amino acid, or a peptidomimetic or other peptide described herein, or (iii) biotin or chemically linked to biotin; R9 is H, -N(R 11 )(R 12 ), or -N + (R 11 )(R 12 )(R 13 )X- , or -N(R 11 )C(O)R 14 is selected from In the formula, R 11 , R 12 , and R 13 are independently H, C 1-4 Alkyl, or C 1-4 fluoroalkyl; R 14 is H, C 1-4 Alkyl, or C 1-4 is a fluoroalkyl; R 15 independently, C 1-4 Alkyl and C 1-4 fluoroalkyl, and X - is a pharmaceutically acceptable anion.

[0125] In some embodiments, Q is O.

[0126] For any of the Markush groups described above, the group may include or exclude any of the compounds listed in the group, and hemichannel blockers for use in the methods of the invention may include or exclude any of these compounds.

[0127] In another embodiment, the analog of Formula I is the compound carabersat ) (N-[(3R,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]-4-fluorobenzamide), or trans-(+)-6-acetyl-4-(S)-(4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzo[b]pyran-3R-ol hemihydrate.

[0128] In certain embodiments, Xiflam and / or its analogs are in the form of the free base or a pharmaceutically acceptable salt. In other embodiments, one or more polymorphs, one or more isomers, and / or one or more solvates of Xiflam and / or its analogs may be used.

[0129] Various other small molecules have been reported to be useful in inhibiting hemichannel activity. See U.S. Patent Application Publication No. 20160177298 to Green et al., Formula II; U.S. Patent Application Publication No. 20160318891 to Savory et al.; and U.S. Patent Application Publication No. 20160318892 to Savory et al., which are incorporated by reference in their entirety as noted above. Hemichannel blockers for use in the methods of the present invention may include or exclude any of these compounds.

[0130] In one embodiment, the invention relates to the use of the pharmaceutical composition, alone or in a kit, package, or other article of manufacture, in a method for treating the diseases, disorders, or conditions described herein, and those characterized by pathological or impaired retinal structure, function, and / or choroidal structure. In some embodiments, the hemichannel blocker is a connexin 43 hemichannel blocker. As noted above, blockers of other connexin hemichannels are also within the scope of the invention.

[0131] In some embodiments, the term "promoiety" refers to a compound that acts as a protecting group to mask a functional group of an active agent, thereby converting the active agent into a prodrug. Typically, a promoiety is attached to a drug via a bond that is cleaved in vivo by enzymatic or non-enzymatic means, thereby converting the prodrug to its active form. In some embodiments, the promoiety may be an active agent. In some embodiments, the promoiety may be attached to a hemichannel blocker molecule, peptide, antibody, or antibody fragment. In some embodiments, the promoiety may be attached to, for example, a peptide, peptidomimetic, or small molecule, or other organic hemichannel blocker. In some embodiments, the promoiety may be attached to a compound of Formula I. In some embodiments, the prodrug may be another hemichannel compound, such as a compound described in U.S. Patent Application Publication No. 20160177298 to Green et al.; U.S. Patent Application Publication No. 20160318891 to Savory et al.; or U.S. Patent Application Publication No. 20160318892 to Savory et al.

[0132] Chemical delivery modification Hemichannel blockers useful in the present invention may be formulated in microparticle (microsphere, MPs) or nanoparticle (nanosphere, NPs) formulations, or both, or in liposomes or implants. Particulate drug delivery systems include nanoparticles (1-999 nm) and microparticles (1-1,000 μm), which are further classified as nanospheres and microspheres, and nanocapsules and microcapsules. In nanocapsules and microcapsules, drug particles or droplets are entrapped in a polymer membrane. Particulate systems offer the advantage of delivery by injection, and their size and polymer composition significantly influence their biological behavior in vivo. Microspheres can remain in the vitreous for much longer periods than nanospheres, allowing microparticles to act like reservoirs after injection. Nanoparticles rapidly diffuse and are internalized into tissues and cells.

[0133]

[0049] Various methods can be used to evaluate the activity or effectiveness of a hemichannel blocker. In one embodiment of the present invention, the effect of hemichannel blocker treatment in a subject is evaluated or monitored using techniques that evaluate retinal structure, retinal function, and choroidal structure and / or function, for example, as described herein.

[0134] The activity of hemichannel blockers may also be evaluated using specific biological assays. The effects of known or potential hemichannel blockers on molecular movement may be identified, evaluated, or screened using the methods described in the Examples below, or other art-known or equivalent methods for determining the passage of compounds through connexin hemichannels. Various methods are known in the art, including dye transfer experiments, such as the transfer of molecules labeled with detectable markers, and membrane penetration of small fluorescent permeable tracers, which are widely used to test the functional status of hemichannels. See, for example, Schlaper, KA, et al. Currently Used Methods for Identification and Characterization of Hemichannels. Cell Communication and Adhesion 15:207-218 (2008). In vivo methods may also be used. For example, Danesh-Meyer, HV, et al. Connexin43 mimetic peptide reduces vascular See methods in Davidson, JO, et al. (2012). Blockade of connexin hemichannels improves outcome in a model of fetal ischemia. Annals of Neurology 71:121-132 (2012).

[0135] One method for use in identifying or assessing the ability of a compound to block hemichannels involves (a) bringing together a test sample and a test system, the test sample including one or more test compounds, and the test system including a system for assessing hemichannel blockade, e.g., in response to the introduction of high glucose, hypoxia, or ischemia into the system, in response to inflammatory mediators, or in response to other compounds or events that induce hemichannel opening, e.g., the addition of a drop of extracellular Ca 2+ and (b) determining, for example, the presence or amount of the dye or other labeled metabolite in the system. Positive and / or negative controls may also be used. Optionally, a predetermined amount of a hemichannel blocker (e.g., Peptide 5 or Xiflam) may be added to the test system.

[0136] Dosage forms and formulations, and administration Unless expressly stated otherwise, all statements regarding administration apply to the hemichannel blockers of the present invention.

[0137] The hemichannel blockers may be dosed, administered, or formulated as described herein.

[0138] In one embodiment, a composition comprising, consisting essentially of, or consisting of one or more hemichannel blockers is administered. Hemichannel blockers may be administered QD, BID, TID, QID, or once a week, for example, QWK (once a week) or BIW (twice a week). They may also be administered monthly using the doses described herein. They may also be administered PRN (i.e., as needed) and HS (before bedtime). It may also be administered at bedtime (hora somni).

[0139] The hemichannel blocker can be administered to a subject in need of treatment. Thus, the present invention provides a formulation that can modulate a connexin hemichannel, such as a connexin 43 hemichannel, or a connexin 45 hemichannel, or a connexin 36 hemichannel, to transiently and site-specifically reduce its open probability.

[0140] The hemichannel blocker may be present in the formulation in a substantially isolated form. The product may be mixed with a carrier or diluent that does not interfere with the intended purpose of the product and still be considered substantially isolated. The product of the present invention may also be in a substantially purified form, in which case the product generally comprises about 80%, 85%, or 90%, e.g., at least about 88%, at least about 90, 95, or 98%, or at least about 99%, of the dry weight of the small molecule hemichannel blocker or preparation.

[0141] The administration of the hemichannel blocker to the subject may be carried out by any means capable of delivering the drug to the target site in the subject's body. For example, the hemichannel blocker may be administered by one of the following routes: oral, topical, systemic (e.g., intravenous, intraarterial, intraperitoneal, transdermal, intranasal, or suppository), parenteral (e.g., intramuscular, subcutaneous, or intravenous or intraarterial injection), implantation (including intraperitoneal, subcutaneous, and intraocular implantation), or infusion via a device such as an osmotic pump or transdermal patch. Exemplary administration routes include: Also reviewed in Binghe, W. and B. Wang (2005). Drug delivery: principles and applications, Binghe Wang, Teruna Siahaan, Richard Soltero, Hoboken, NJ Wiley-Interscience, c2005. In one embodiment, the hemichannel blocker is administered systemically. In another embodiment, the hemichannel blocker is administered locally. In another embodiment, the hemichannel blocker is administered, for example, topically onto the eye or directly into the eye.

[0142] In some aspects, hemichannel blockers may be provided as or in conjunction with an implant. In some aspects, the implant may provide sustained, controlled, or extended release delivery, with or without centralized administration. In some embodiments, microneedles, needles, iontophoresis devices, or implants may be used to administer the hemichannel blockers. The implant may be, for example, a dissolvable disc material, such as that described in S. Pflugfelder et al., ACS Nano, 9(2), pp. 1749-1758 (2015). In some aspects, hemichannel blockers of the present invention, e.g., connexin 43 hemichannel blockers, may be administered via intracerebroventricular, intrathecal, extradural, subdural, and / or epidural routes.

[0143] The hemichannel blocker may be administered once, multiple times, or periodically. It may also be administered PRN (as needed), or on a predetermined schedule, or both. In some embodiments, the hemichannel blocker is administered daily, weekly, monthly, bimonthly, or quarterly, or any combination of these intervals. For example, treatment may be administered daily for a period of time, followed by weekly and / or monthly administration. Other methods of administering the blocker are also discussed herein. In one embodiment, the hemichannel blocker is administered to a patient in an amount sufficient to treat the patient on days 1 through 5, 10, 30, 45, 60, 75, 90, or 100-180.

[0144] Hemichannel blockers, such as compounds of Formula I, such as Xiflam, or analogs or prodrugs of any of the aforementioned compounds, or compounds of Formula II, may be administered alone or in combination with one or more additional ingredients, and may be formulated in pharmaceutical compositions containing one or more pharmaceutically acceptable excipients, diluents, and / or carriers. In some embodiments, hemichannel blockers, such as compounds of Formula I, such as Xiflam (tonabersat), or analogs or prodrugs of any of the aforementioned compounds, or compounds of Formula II, may be orally administered in a composition containing food. In some embodiments, the food is peanut butter or hazelnut-based cream. Without being bound by theory, relatively hydrophobic compounds of Formula I or Formula II, including tonabersat, are encapsulated in the emulsified fat of food (e.g., peanut butter) and then slowly released, thereby providing a long-term therapeutic duration.

[0145] As used herein, the term "pharmaceutically acceptable diluents, carriers, and / or excipients" is intended to include substances useful in preparing pharmaceutical compositions that may be co-administered with a compound of Formula I, such as Xiflam, any analog of said compound, or a compound of Formula II, while performing its intended function and are generally safe, non-toxic, and not biologically or otherwise undesirable. Pharmaceutically acceptable diluents, carriers, and / or excipients include those suitable for veterinary and human pharmaceutical use. Suitable carriers and / or excipients will be readily apparent to those skilled in the art, taking into account the properties of a compound of Formula I, such as Xiflam, and any analog of said compound. However, by way of example, diluents, carriers, and / or excipients include solutions, solvents, dispersion media, retardants, polymeric and lipid agents, emulsions, and the like. Further examples include suitable liquid carriers, particularly for injectable solutions, such as water, saline, aqueous dextrose, etc., with isotonic solutions being preferred for intravenous, intrathecal, and intracisternal administration, and vehicles such as liposomes being particularly suitable for administering the agent.

[0146] The compositions may take the form of any standard, known dosage form, including tablets, pills, capsules, semisolids, powders, sustained-release formulations, solutions, suspensions, elixirs, aerosols, injectable liquids, gels, creams, transdermal delivery devices (e.g., transdermal patches), inserts for organs such as the skin or eye, or any other suitable compositions. Those skilled in the art to which the present invention pertains will readily recognize, without undue experimentation, the most suitable dosage form, taking into account the nature of the condition being treated and the nature of the active agent being used. It should be understood that one or more of the compounds of Formula I, such as Xiflam, and analogs of any of the foregoing compounds, and / or hemichannel blockers, such as compounds of Formula II, may be formulated in a single composition. In certain embodiments, preferred dosage forms include injectable solutions, implants (preferably sustained-release, controlled-release, or sustained-release implants with or without bolus administration), and oral formulations.

[0147] Compositions useful in the present invention may contain any suitable level of a compound of Formula I, such as Xiflam, and analogs of any of the foregoing compounds, and / or a hemichannel blocker, such as a compound of Formula II, taking into account the dosage form and mode of administration. However, by way of example, the compositions used in the present invention may contain from about 0.1% to about 99% by weight, preferably from about 1% to about 60% by weight, of the hemichannel blocker, depending on the method of administration.

[0148] In addition to standard diluents, carriers, and / or excipients, compositions according to the present invention may be formulated with one or more additional components, or in such a manner enhance the activity or bioavailability of hemichannel blockers, such as compounds of formula I, e.g., Xiflam, and analogs of any of the foregoing compounds, and / or compounds of formula II. The compositions may be formulated to help protect the integrity of the compositions or extend their half-life or shelf life, to release slowly upon administration to a subject, or to provide other desirable benefits, for example. For example, sustained-release vehicles include macromers, poly(ethylene glycol), hyaluronic acid, poly(vinylpyrrolidone), or hydrogels. By way of further example, the compositions may also include preservatives, solubilizers, stabilizers, humectants, emulsifiers, sweeteners, colorants, flavoring agents, coating agents, buffers, etc. Those skilled in the art to which this invention pertains will be able to identify additional additives that may be desirable for particular purposes.

[0149] As mentioned above, hemichannel blockers may be administered by sustained release systems. Suitable examples of sustained release compositions include semipermeable polymer matrices in the form of articles such as films or microcapsules. Sustained release matrices include polylactides (U.S. Pat. No. 3,773,919, EP 58,481), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, poly(2-hydroxyethyl methacrylate), ethylene vinyl acetate, or poly-D-(-)-3-hydroxybutyric acid (EP 133,988). Sustained release compositions also include liposome-encapsulated compounds. Liposomes containing hemichannel blockers may be prepared by known methods, including those described in DE 3,218,121; EP 52,322; EP 36,676; EP 88,046; EP 143,949; EP 142,641; Japanese Patent Application No. 83-118008; U.S. Patent Nos. 4,485,045 and 4,544,545; and EP 102,324. Typically, the liposomes are small (approximately 200-800 angstroms) unilamellar liposomes with a lipid content greater than about 30 mole percent cholesterol, with the selected ratio adjusted for the most effective therapeutic approach. For example, sustained release delivery using PGLA nanoparticles or microparticles or an in situ ion-activated gelation system may be used.

[0150] It is further contemplated that hemichannel blocker pharmaceutical compositions for use in accordance with the present invention may be formulated with additional active ingredients or agents that may, in certain instances, be of therapeutic or other benefit to the subject. Those skilled in the art to which the present invention pertains will recognize appropriate additional active ingredients in light of the description of the present invention herein and the nature of the disorder being treated.

[0151] It is further contemplated that hemichannel blocker pharmaceutical compositions for use in accordance with the present invention may be formulated in candies or food products, for example, as "gummy" pharmaceuticals.

[0152] The compositions are described, for example, in Gennaro AR: Remington: The Science and Practice of Pharmacy, 20 th ed., Lippincott, Williams & Wilkins, 2000. However, by way of further example, the information provided in US2013 / 0281524 or US5948811 may be used.

[0153] Any container suitable for storing and / or administering pharmaceutical compositions may be used for the hemichannel blocker products for use in the present invention.

[0154] Hemichannel blockers, e.g., connexin 43 hemichannel blockers, may in some embodiments be formulated to provide controlled and / or sequestered release to the site of administration. In some embodiments of the invention, the formulation may be an immediate release, or an extended or sustained release dosage form. In some embodiments, the dosage form may be an extended release dosage form and / or sustained release dosage form. The dosage form may include both an immediate-release dosage form combined with a sustained-release dosage form. In some embodiments, both immediate release and sustained and / or long-term release of the hemichannel blocker can be obtained by mixing the hemichannel blocker in an immediate-release form. In some embodiments of the present invention, the hemichannel blocker is, for example, a connexin 43 blocker or other hemichannel blocker disclosed herein. In some embodiments of the present invention, the dosage form may be an implant, such as a biodegradable implant or a non-biodegradable implant.

[0155] The present invention includes methods for modulating hemichannel function to treat, reverse or substantially reverse, or ameliorate a variety of disorders. The methods of the invention involve administering a hemichannel blocker alone, or, if desired, in combination with one or more other agents or therapies.

[0156] Administration of the hemichannel blocker, and optionally one or more other active agents, may occur at any time during the progression of the disorder, or at any time before or after the onset of the disorder or one or more symptoms of the disorder. In one embodiment, the hemichannel blocker is administered periodically over an extended period of time to aid in the ongoing management or reversal of symptoms. In another embodiment, the hemichannel blocker is administered periodically over an extended period of time or lifelong to prevent or delay the onset of the disorder or to eliminate the disorder.

[0157] In some embodiments, a hemichannel blocker, e.g., a connexin 43 hemichannel blocker (e.g., a compound of Formula (I) including tonabersat, or a compound of Formula (II)), can be administered as a pharmaceutical composition comprising one or more particles. In some aspects, the pharmaceutical composition can be, for example, an immediate-release formulation or a controlled-release formulation, e.g., delayed-release particles. In other aspects, the hemichannel blocker can be formulated in a particulate formulation of one or more particles for selective delivery to the area to be treated. In some embodiments, the particle can be, for example, a nanoparticle, nanosphere, nanocapsule, liposome, polymeric micelle, or dendrimer. In some embodiments, the particle can be a microparticle. The nanoparticle or microparticle can comprise a biodegradable polymer. In other embodiments, the hemichannel blocker is prepared or administered as an implant or matrix, or formulated to provide sequestered release at the site of administration. In some embodiments, the pharmaceutical composition of a hemichannel blocker, e.g., a connexin 43 hemichannel blocker (e.g., a compound of Formula (I) comprising tonabersat, or a compound of Formula (II)) does not comprise microparticles.

[0158] In some embodiments, the hemichannel blocker formulated as described is, for example, a connexin 37, connexin 40, connexin 43, or connexin 45 hemichannel blocker. Connexin 36, connexin 37, connexin 40, connexin 43, or connexin 45 blockers are preferred. Most preferred blockers are connexin 36 and connexin 43 hemichannel blockers. Particularly preferred blockers are connexin 43 hemichannel blockers. As used herein, "matrix" includes matrices such as polymeric matrices, biodegradable or non-biodegradable matrices, and other carriers useful for fabricating implants and structures adapted for delivery of hemichannel blockers. Implants include reservoir implants and biodegradable matrix implants.

[0159] Connexin hemichannel blocker combination products / kits In another embodiment of the present invention, an article of manufacture or "kit" is provided containing materials useful for treating the diseases and disorders described above. The kit comprises a container containing, consisting essentially of, or consisting of a connexin hemichannel blocker. The kit may further comprise a label or package insert on or associated with the container. The term "package insert" refers to a therapeutic agent. This term refers to instructions typically included in commercial packaging for a therapeutic product, containing information about the indications, uses, dosage, administration, contraindications, and / or warnings for using the therapeutic product. Suitable containers include, for example, bottles, vials, syringes, blister packs, and the like. The container may be formed from a variety of materials, such as glass or plastic. The container holds a hemichannel blocker or a formulation thereof effective for treating a condition and may have a sterile access port (e.g., the container may be an intravenous solution bag or a vial with a stopper pierceable by a hypodermic injection needle). The label or package insert indicates that the composition is used for the medical treatment of a selected condition, such as any of the diseases, disorders, and / or conditions described or referenced herein. The label or package insert may also indicate that the composition can be used to treat other disorders. Alternatively, or in addition, the product may further comprise a second container containing a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0160] The kit may further comprise instructions for administering the hemichannel blocker to a patient in need thereof.

[0161] Also provided are articles of manufacture comprising, consisting essentially of, or consisting of a container comprising a compound, composition, or formulation of a hemichannel blocker and instructions for use for treating a subject. For example, in another aspect, the invention includes an article of manufacture comprising, consisting essentially of, or consisting of a container containing a therapeutically effective amount of one or more connexin hemichannel blockers, including small molecules, together with instructions for use, including use for treating a subject.

[0162] In some aspects, the article of manufacture may include a matrix containing one or more connexin hemichannel blockers, eg, small molecule hemichannel blockers, alone or in combination.

[0163] Dosage, volume, and concentration Of course, the dose, duration of administration, and overall administration regimen of the administered hemichannel blocker may vary from subject to subject, depending on variables such as the target site of delivery, the severity of any symptoms of the subject being treated, the type of disorder being treated, the size of the unit dose, the selected mode of administration, and the age, sex, and / or general health of the subject, as well as other factors known to those skilled in the art.

[0164] Also included herein are methods for enhancing the survival and restoration or recovery of retinal structure and / or function and choroidal structure and / or function in a subject in need thereof, comprising administering to the subject an effective amount of a hemichannel blocker, such as N-[(3S,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]-3-chloro-4-fluorobenzamide (Xiflam). In some embodiments, the survival-promoting amount is about 10 to about 200 mg per day, or in some embodiments, about 3.5 to 350 mg per day. In other embodiments, the survival-promoting amount is about 20 to about 100 mg per day. These amounts may be administered in a single dose or in divided doses, e.g., twice daily. A dose ranging from about 0.5 to about 5 mg / kg per day is preferred. Doses can be, for example, about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4., 4.5, 4.6, 4.7, 4.8, 4.9, or about 5.0 mg / kg per day, or any two of the listed doses. It may be any range between them.

[0165] Particularly preferred daily dose is about 1.4mg / kg per day, in single dose or divided dose (for example, BID).Therefore, for example, for the subject with body weight of about 70kg, 90kg or 100kg, the daily dose is about 98mg, about 126mg or about 140mg, respectively.These doses provide effective peak steady-state concentration of hemichannel blocker, for example, Xiflam, after about 10 days.

[0166] For efficacy and patient convenience and compliance, other doses and useful weekly, monthly, and implant administrations and dosing regimens have also been developed and are provided herein. Some preferred weekly doses range from about 2 mg / kg to about 50 mg / kg. The weekly dose may be, for example, about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or about 50 mg / kg, or any range between any two of the listed weekly doses. QWK administration of about 42 to about 47 mg / kg provides effective trough hemichannel concentrations with about 4 to 5 predicted half-lives per week for hemichannel blockers, such as hemichannel blockers of Formula I or Formula II, e.g., Xiflam, for practicing the methods of the present invention related to retinal and / or choroidal structure and function. Plasma peak concentrations at doses of about 42 to about 47 mg / kg are higher than effective trough concentrations but are tolerable. Doses of 25 to 100 mg / kg are also effective when administered monthly.

[0167] In some embodiments, the residual enhancement dose is about 4.5 to about 450 mg administered once weekly (QWK). These doses include doses ranging from about 4.5 to about 45 mg QWK, and about 45 to 450 mg QWK, or any dose range therebetween. A dose obtained by multiplying any of the weekly doses disclosed herein by the patient's body weight (e.g., 60, 65, 70, 75, 80, 85, 90, 95, or 100 kg) may also be used.

[0168] In another weekly QWK administration embodiment, the hemichannel blocker compound is administered in a sustained-, extended-, or controlled-release oral or implant formulation, with or without a 10-20% or other desired dose concentration. Implant formulations, such as intraocular implant formulations, are preferred for placement in sustained-, extended-, or controlled-release oral or implant formulations.

[0169] Doses of 3.5-350 mg per day, 10-200 mg per day, or 20-100 mg per day may be used to restore or recover retinal structure and / or function and / or restore or recover choroidal structure and / or function. In some embodiments, oral doses of 15-150 mg, 25-250 mg, 40-400 mg, or 80-800 mg of the anti-hemichannel compound are administered in single or divided doses to promote survival of retinal and / or choroidal function, restore or recover retinal structure and / or function, or restore or recover choroidal structure and / or function. In other embodiments, oral doses of 100-500 mg, 500-1000 mg, or 1000-2000 mg are administered in single or divided doses. The divided doses are administered twice daily, twice daily, or twice daily, or quarter-weekly. Xiflam is currently the preferred compound for oral administration.

[0170] Importantly, weekly administration is useful in restoring or restoring retinal structure and / or function, or in restoring or restoring choroidal structure and / or function. For the restoration or recovery of retinal and / or retinal function, or for the restoration or recovery of choroidal structure and / or function, high doses, such as 500 mg to 2000 mg, or amounts between these doses, such as 750 mg, 1000 mg, 1250 mg, 1500 mg, and 1750 mg, may be administered once a week or even once a month. Xiflam is currently the preferred compound for oral administration in these amounts. Other QWK doses include those between about 2500 mg and 5500 mg, with preferred doses being about 2900 mg, 3700 mg, 4200 mg, 3300 mg, 4200 mg, and 4700 mg QWK, and all doses in between. These doses are also effective when administered monthly.

[0171] Examples of effective doses that can be used to treat the diseases, disorders, or conditions referenced herein are described below. Other exemplary doses range from about 0.1 to about 5.0 mg / kg, including, for example, 0.2 to 3.0 mg / kg, or 0.2 to 2 mg / kg, and 0.2 to 1.0 mg / kg, or 0.2 to 0.5 mg / kg. Some exemplary daily doses, or other regular doses, range from about 10 to 250 mg per dose, including, for example, about 20 to 25 mg per dose, about 25 to 50 mg per dose, 20 to 40 mg per dose, about 50 to 75 mg per dose, about 75 to 100 mg per dose, and about 100 to 250 mg per dose, including doses of 20, 50, 100, and 150 mg per dose, or any specific dose within one of these mg ranges of drug per kg of body weight. In some embodiments, the circulating concentration of the hemichannel blocker (including compounds of Formula (I), including tonabersat, and compounds of Formula (II)) in a subject to which the hemichannel blocker has been administered is in the range of about 5 micromolar to about 200 micromolar, about 7 micromolar to about 100 micromolar, or about 10 micromolar to about 90 micromolar.

[0172] As described above, the dose of a hemichannel blocker, such as a connexin 37, 40, or 43 hemichannel blocker, may be administered in a single application or in divided applications. The dose may be administered once or repeatedly. Typically, the application is repeated weekly, every other week, or every three weeks, monthly, or every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months, or more, as needed to prevent, delay, or treat any disease, disorder, or condition described herein. The dose may also be applied every 12 hours to 7 days, or more. For example, the dose may be applied 12 hours, or 1, 2, 3, 4, 5, 6, or 7 days, or between any two of these times, or at any time interval between 12 hours and 7 days. The connexin 43 hemichannel blocker may be administered for, for example, up to 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, or 26 weeks. For some indications, more frequent administration may be employed. In some embodiments, the hemichannel blocker may be administered daily at an initial dose level for a first period, followed by daily administration at increased dose levels for an additional period.

[0173] Manufacturing and Purity Small molecule hemichannel blockers, including those of Formula I and Formula II, can be prepared as previously described.

[0174] In some embodiments, the formulations of the present invention are substantially pure. By substantially pure, it is meant that the formulation contains less than about 10%, 5%, or 1%, and preferably less than about 0.1%, of any impurities. In some embodiments, the total impurities, including metabolites of the connexin 43 modulating agent, are 1-15% or less. In some embodiments, the total impurities, including metabolites of the connexin 43 modulating agent, are 2-12 ... The total impurities, including metabolites, of the connexin 43 modulating agent are 3 to 11% or less. In another embodiment, the total impurities, including metabolites of the connexin 43 modulating agent are 4 to 10% or less. [Example]

[0175] The experiments described in these Examples evaluated and demonstrated the ability of treatment with doses and dosing regimens of hemichannel blockers to maintain choroidal thickness, maintain retinal thickness, and preserve and restore retinal function in animals with diabetic retinopathy.

[0176] Example 1 method Retinal light damage model for dry age-related macular degeneration - A bright light damage model was developed and performed as described in a previous study. Mat Nor N, Guo CX, Rupenthal ID, Chen YS, Green CR, Acosta ML. Sustained Connexin43 Mimetic Peptide Release From Loaded Nanoparticles Reduces Retinal and Choroidal Photodamage.Invest Ophthalmol Vis Sci.2018;59:3682-93;Guo CX,Mat Nor MN,Danesh-Meyer HV,Vessey KA,Fletcher EL,O'Carroll SJ,et al.Connexin43 Mimetic Peptide Improves Retinal Function and Reduces Inflammation in a Light-Damaged Albino Rat Model. Invest Ophthalmol Vis Sci. 2016;57:3961-73; Guo CX, Tran H, Green CR, Danesh-Meyer HV, Acosta ML. Gap junction proteins in the light-damaged albino rat. Mol Vis. 2014;20:670-82; Noell WK, Walker VS, Kang BS, Berman S. Retinal damage by light in rats. Invest Ophthalmol. 1966;5:450-73. The light-damaged rat model was chosen because it allows direct comparison of the drug in question with other drugs. Kim Y,Griffin JM,Nor MNM,Zhang J,Freestone PS,Danesh-Meyer HV,et al.Tonabersat Prevents Inflammatory Damage in the Central Nervous System by Blocking Connexin43 Hemichannels.Neurotherapeutics.2017;14:1148-65;Mat Nor N,Guo CX,Rupenthal ID,Chen YS,Green CR, Acosta ML, supra; Guo CX, Mat Nor MN, Danesh-Meyer HV, Vessey KA, Fletcher EL, O'Carroll SJ, et al., supra. This model demonstrates pathological factors of AMD (oxidative stress and inflammation) and provides measurable endpoints (including retinal electrical function). A drawback of this model, as with other rodent models, is that it does not develop drusen. All experimental procedures were approved by the University of Auckland's Animal Ethics Committee under approval number 001462 and conformed to the Association for Research in Vision and Ophthalmology (ARVO) statement regarding the use of animals in ophthalmic research. Six- to eight-week-old albino Sprague-Dawley (SD) rats (200-250 g, male or female) were used. Adult SD rats were exposed to 24 hours of continuous bright light, consistently starting at 9:00 AM to minimize potential time-of-day variations. Light exposure was performed two animals at a time to prevent rats from using each other as a shield to escape. The LD protocol and interventions were repeated until a sufficient number of individuals were obtained for each dose group (n = 7 per group). A fluorescent lamp (Philips Master TLD 18W) was placed directly above the animal cage. A light source ( / 965; Koninklijke Philips Electronics NV, China) was used to generate a light intensity of 2700 lux. The lamp was cooled and emitted broadband light with wavelengths from 380 to 760 nm, with an average intensity above the cage of 120 W / m². Animals moved freely within their cages and had free access to food and water. Baseline electroretinogram (ERG) readings and optical coherence tomography (OCT) images were collected before light injury. After light exposure, animals were returned to normal light-dark cycle conditions (12 h light, 174 lux, and 12 h darkness, <62 lux) for 24 h, 1 week, or 2 weeks (and for one group, 3 months).

[0177] Tonabelsat Treatment of Light-Injured Rats - LD rats were randomly assigned to low, medium, or high doses of tonabelsat (n=7 per group). Tonabelsat mixtures in peanut butter were prepared freshly for each experiment. Three oral doses of tonabelsat were tested (n=7 per group). Animals were followed for up to two weeks after injury, with three animals from the highest dose group separated for histological analysis and four animals followed for up to three months after injury. A vehicle-only control group of 10 animals was included. Groups of rats maintained for three months were maintained with drug- and vehicle-treated animals in separate cages but under the same light conditions. Taking into account the dose levels of previous unsuccessful human trials, tonabersat was given to animals in peanut butter at 0.26 mg / kg (average 0.08 mg delivered, estimated circulating concentration 10 μM), 0.8 mg / kg (average 0.24 mg delivered, estimated circulating concentration 30 μM), or 2.4 mg / kg (average 0.72 mg delivered, estimated circulating concentration 90 μM). Silberstein SD. Tonabersat, a novel gap-junction Modulator for the prevention of migraine. Cephalalgia. 2009;29 Suppl 2:28-35; Dahlof CG, Hauge AW, Olesen J. Efficacy and safety of tonabersat, a gap-junction modulator, in the acute treatment of migraine: a double-blind, parallel-group, randomized study. Cephalalgia. 2009;29 Suppl 2:7-16; Goadsby PJ, Ferrari MD, Csanyi A, Olesen J, Mills JG, Tonabersat TONSG. Randomized, double-blind, placebo-controlled, proof-of-concept study of the cortical spreading depression inhibiting agent tonabersat in migraine prophylaxis. Cephalalgia. 2009;29:742-50. Animals were fed immediately before the light exposure period. Animals that did not receive the drug were excluded from the study (total number of experiments: n = 29, drug- and vehicle-treated animals). Although researchers were aware of the treatment groups at the time of treatment, the groups were subsequently randomized before statistical comparisons were made. This means that analyses were conducted without knowledge of which animals were treated or control. Briefly, adult rats were dark-adapted overnight, and ERG data were collected. Animals were given either vehicle or tonabersat prior to intense light exposure. After two weeks, animals were again evaluated with ERG and OCT, and tissue collection proceeded immediately. However, four rats from the high-dose group were studied for an additional three months.

[0178] Hyperglycemic Rat Diabetic Retinopathy Model - A spontaneously hyperglycemic strain of SD rats that developed clinical signs of diabetic retinopathy within 4 weeks of birth was identified and isolated within the Vernon Jansen Animal Research Unit, Faculty of Medical and Health Sciences, University of Auckland. Identifying these rats exhibiting hyperglycemia and microaneurysms provided an opportunity to treat a complex, chronic disease model and evaluate treatment efficacy based on objective, measurable endpoints, even in the absence of precise information about disease pathogenesis. Breeding was performed over three generations, and eyes were screened for abnormalities between 4 and 8 weeks of age. Additional information about these rats can be found in the Supplementary Material. Glucose levels were measured in non-fasted rats using a Freestyle Optium Glucometer (Abbott Laboratories Ltd., UK) and Freestyle Optium glucose strips (Lee JJ, Yi HY, Yang JW, Shin JS, Kwon JH, Kim CW. Characterization of streptozotocin-induced diabetic rats and pharmacodynamics of insulin formulations. Biosci Biotechnol Biochem. 2003;67:2396-401).

[0179] Ten rats per group (10 normal SD rats and 10 hyperglycemic rats) were selected and grown to 5 weeks of age and evaluated using OCT and ERG. The hyperglycemic rat group was then divided into two subgroups of 5 rats each. One subgroup received a low dose of 0.28 mg / kg of tonabelsat in 0.5 g of peanut butter for 14 days from weeks 5 to 7, while the other subgroup received 0.5 g of peanut butter alone. All animals were evaluated again using ERG and OCT at 8 weeks of age, after which the animals were euthanized and their eyes were harvested for immunohistochemical analysis. Data groups were randomized, and statistical comparisons were then performed. In summary, normal SD rats and hyperglycemic rats were analyzed using OCT and ERG at 5 weeks of age. The hyperglycemic rats were then divided into two groups and given either vehicle or tonabelsat for 14 days between weeks 6 and 7 of age. At 8 weeks of age, animals were again evaluated with ERG and OCT and tissues were collected for immunohistochemistry, but four tonabersat-treated rats were left until 3 months of age before final ERG and OCT and tissue collection.

[0180] Evans Blue Dye Assessment of Vascular Leakage - To investigate whether microaneurysms and giant aneurysms (observed using optical coherence tomography) in the retina of hyperglycemic rats reflect sites of vascular leakage, 3-month-old rats were perfused with Evans Blue dye as previously reported. Cai S, Yang Q, Hou M, Han Q, Zhang H, Wang J, et al. Alpha-Melanocyte-Stimulating Hormone Protects Early Diabetic Retina from Blood-Retinal Barrier Breakdown and Vascular Leakage via MC4R. Cell Physiol Biochem. 2018;45:505-22. Briefly, Evans Blue dye (30 mg / ml, Sigma-Aldrich, USA) was dissolved in normal saline and filtered. 45 mg / kg of dye was delivered as an injection into the tail vein of normal SD and hyperglycemic rats and allowed to circulate for 2 hours. While the rats were deeply anesthetized, the eyes were enucleated and then euthanized by rapid intracardiac injection of 3 M KCl. The entire posterior segment optic nerve cup was fixed in 4% paraformaldehyde for 30 minutes, and the retina was removed and flattened. Evans blue was stimulated at a wavelength of 559 nm and visualized by red fluorescence emission using an Olympus FluoView FV1000 (Olympus Corporation, Tokyo, Japan).

[0181] Electroretinogram recording procedures were performed as previously reported. Vessey KA, Wilkinson-Berka JL, Fletcher EL. Characterization of retinal function and glial cell response in a mouse model of oxygen-induced retinopathy. J Comp Neurol. 2011;519:506-27. SD rats were generally dark-adapted for 12-14 hours overnight, followed by ERG recording. For dry AMD, baseline ERGs were recorded for all groups before and after light injury (24 hours, 1 week, 2 weeks, and 3 months after bright light). For the DR model, ERGs were recorded at 5 weeks of age to compare retinal function between normal SD and hyperglycemic rats. Tonabersat-treated hyperglycemic rats and vehicle-treated SD rats were also recorded. Control hyperglycemic rats were evaluated again at 8 weeks of age. After dark adaptation, rats were anesthetized by intraperitoneal injection of a combination of ketamine (75 mg / kg, Parnell Technologies, New Zealand) and domitor (0.5 mg / kg, Pfizer, New Zealand). During manipulation of dark-adapted animals, dim red light was generated by a light-emitting diode (λmax = 650 nm). During ERG recording, the cornea was kept hydrated using 1% sodium carboxymethylcellulose (Celluvisc, Allergan, USA). ERGs from both eyes were recorded using gold ring electrodes (Roland Consult Stasche & Finger GmbH, Germany). A U-shaped active electrode was maintained in contact with the center of the cornea. A V-shaped inert electrode was hooked around the front teeth and placed in contact with the moist tongue. Normothermia was maintained by placing the animals on a 37°C heating pad to avoid temperature-induced ERG amplitude fluctuations. Full-field ERG responses were elicited by twin flashes (0.8 ms inter-stimulus interval) generated from a photographic flash unit (Nikon SB900 flash, Japan) via a Ganzfeld sphere. An integrating sphere with a diameter of approximately 650 mm and a white interior was used to reflect the flash light across the retina. The flash intensity ranged from -2.9 to 2.1 log cd.s / m² and was attenuated using a neutral density filter (Kodak Wratten, Eastman Kodak, USA) to obtain light intensities of -3.9, -2.9, -1.9, 0.1, 1.1, 1.6, 1.8, and 2.1 log cd.s / m². Flash intensities were calibrated using an IL1700 research radiometer (UV Process Supply Inc., USA). This study utilized a twin-flash palladium system to separate the rod and cone pathways. Paired flashes of identical luminous energy were delivered from the flash unit. The mixed rod and cone responses were recorded after the first flash, and the response from the second flash recorded and represented the function from the cones alone. The rod PIII response was derived by digitally subtracting the cone response from the first mixed response.The PIII component of the ERG is a direct reflection of rod photocurrents, and the slope of the a-wave is better interpreted by considering information about rod photocurrents after fitting these responses to a computational model. To do so, ERG data at maximum light levels are fitted to a model of the rod response that assumes the initial response amplitude rises linearly with intensity, and then saturated to reveal PII (bipolar cell component) and PIII (photoreceptor component). Through this separation of rod PII and PIII, we can confirm that the a- and b-wave ERG data correspond to changes in both the cone and rod pathways. Oscillatory potentials (OPs) are another way to examine inner retinal function. OPs were separated by subtracting the raw b-wave from rod PII. Weymouth AE, Vingrys AJ. Rodent electroretinography: methods for extraction and interpretation of rod and cone responses. Prog Retin Eye Res. 2008;27:1-44. The summed amplitude of OP2, 3, and 4 was analyzed. Recordings were performed in a Faraday cage to reduce electrical noise. The resulting ERG signals were amplified 1,000 times by a Dual Bio Amp (AD Instruments, Australia), and the waveforms were analyzed using Scope software (AD Instruments). ERGs were recorded using a MRI scanner (Daniel Instruments, New Zealand) and analyzed using published algorithms for a- and b-wave amplitudes for each eye. Guo CX, Mat Nor MN, Danesh-Meyer HV, Vessey KA, Fletcher EL, O'Carroll SJ, et al., supra; Vessey KA, Wilkinson-Berka JL, Fletcher EL, supra. To achieve 80% power and an alpha of 5%, we determined that ERG studies required a sample size of 5.

[0182] Optical coherence tomography - Spectral domain optical coherence tomography (SD-OCT; Micron IV; Phoenix Research Laboratories, USA) OCT was employed to obtain information on the morphology of retinal layers in vivo. OCT was performed immediately after ERG recordings were acquired, under anesthesia and with 1% tropicamide (Bausch & Lomb New The study was performed on animals with dilated pupils using a 37°C heating pad (Alcon Laboratories Pty Ltd, Australia). Guo CX, Mat Nor MN, Danesh-Meyer HV, Vessey KA, Fletcher EL, O'Carroll SJ, et al., supra. Rats were placed on a 37°C heating pad to maintain body temperature and prevent the development of cooling cataracts. The eye was covered with Poly Gel (containing 3 mg / g of Carbomer; Alcon Laboratories Pty Ltd, Australia), and the retina was imaged by contacting the OCT lens with the gel. StreamPix 6 software, version 7.2.4.2 (Phoenix Research Laboratories, USA) was used for image acquisition. SD-OCT horizontal B-scans had an axial resolution of 2 μm and consisted of 1024 pixels per A-scan. Ten B-scans, acquired 2 mm from the optic nerve dorsal to the retina, were acquired and averaged. Images were analyzed using InSight software, version 1.1.5207 (Phoenix Research Laboratories, USA). Choroidal thickness was measured from the hyperreflective Bruch's membrane to the choroid-sclera interface. Outer nuclear layer (ONL) thickness was measured from the external limiting membrane (OLM) to the outer plexiform layer (OPL) interface.

[0183] Tissue Collection and Processing. At the end of the final OCT recording, rats were deeply anesthetized using a combination of ketamine (75 mg / kg, Parnell Technologies, New Zealand) and Domitor (0.5 mg / kg, Pfizer, New Zealand). Animals were transcardially perfused with saline for 2–3 minutes, followed by 4% paraformaldehyde in 0.1 M phosphate buffer, pH 7.4 (PB) for 30 minutes. Eyes were dissected from the orbit, and the eyecups were further immersion-fixed in 4% paraformaldehyde, followed by rinsing in PB for 30 minutes. Tissues were then cryoprotected by passing them through 10% and 20% sucrose / PB solutions for 30 minutes each at room temperature, followed by immersion in 30% sucrose / PB overnight at 4°C. The tissues were then embedded in optimum cutting temperature compound (Sakura Finetek, Torrance, USA) for vertical cryosectioning (16 μm section thickness) using a Leica CM3050 S cryostat (Leica, Germany). Sections were collected onto Superfrost Plus slides (Labserv, New Zealand) for immunohistochemical labeling. For DR animals, we collected the spleen, pancreas, liver, heart, and kidney from randomly selected vehicle-injected animals (see Supplementary Information).

[0184] Immunohistochemical labeling of tissue sections: Frozen tissue sections were air-dried at room temperature for 10–15 min and washed with 0.1M PB. Sections were surrounded by PAP pen (Invitrogen, New Zealand) to form incubation wells and blocked with a solution of 6% normal goat serum or donkey serum (Invitrogen, USA), 1% bovine serum albumin (BSA), and 0.5% Triton X-100 in 0.1M PB for 1 h at room temperature. Primary antibodies included rabbit anti-connexin 43 (1:1000, Cat C6219, Sigma-Aldrich, USA) and mouse anti-Iba-1 (ionized calcium-binding adapter antibody), which is specifically expressed by microglial cells. Antibodies included primary antibody 1 (1:250, Cat. Ab5076, Abcam, USA), and mouse anti-GFAP (1:1000, Cat. C9205, Sigma-Aldrich, USA) for astrocytes and Müller cells. Sections were incubated with the primary antibodies overnight at room temperature and then washed four times for 15 minutes each in 0.1M PB. Secondary antibodies, goat anti-rabbit or goat anti-mouse conjugated with Alexa™ 488 or Alexa™ 594 (Invitrogen, Australia), were applied at a dilution of 1:500 for 2-3 hours at room temperature in the dark. Slides were then stained with the primary antibodies. Sections were thoroughly washed with 0.1 M PB, cell nuclei were stained with DAPI (1:1000; Sigma-Aldrich, USA), and then coverslipped with anti-fading medium (Citifuor Ltd, UK). Coverslips were sealed with nail polish. Sections were imaged using an Olympus FluoView FV1000 confocal laser scanning microscope equipped with excitation lasers at wavelengths of 405, 473, and 559 nm (Olympus Corporation, Japan).

[0185] Statistical analysis - Graphing and statistical analysis were performed using GraphPad Prism 5 (GraphPad Software, Inc., USA). All data are expressed as mean ± standard error of the mean (SEM). Functional and morphological data were compared using analysis of variance (ANOVA) with an alpha value of 0.05. To compare the effects of stimulation intensity, ERG response analysis used a two-way ANOVA followed by Bonferroni's post-hoc test. For control and light-damaged animals, a one-way ANOVA followed by Tukey's test was used for ERG responses at an intensity of 2.1 log cd.s / m2, and was also used for OCT data analysis. Statistical analysis of rod PII and PIII was performed using an unpaired t-test with Welch's correction, assuming normal mean distribution across samples.

[0186] Example 2 In an animal light injury model of retinal deterioration, treatment with hemichannel blockers preserved choroidal thickness, retinal thickness, and restored retinal function. The mixed a-wave ERG data plotted against the range of light intensities tested produced negative waves that increased as flash intensity increased from low to mid-range levels. The mixed b-wave ERG response was positive and consistent across most flash intensities.

[0187] After 24 hours of light exposure, the ERG responses of albino rats were significantly attenuated with a maximum a-wave amplitude of −100 μV. ERG data are shown in Figure 1 for the vehicle-fed animals at 2 weeks post-injury and for each of the three treatment dose groups at 24 hours, 1 week, and 2 weeks post-light injury.

[0188] At 24 hours after light exposure, there were no differences between the vehicle control group and any of the three tonabersat dose groups (Figure 1).

[0189] However, significant improvements in mixed a-wave amplitude compared to the light-injured control group were seen 1 week after treatment in both 0.26 mg / kg and 0.8 mg / kg treated animals (p<0.01, Figure 1B-C), and in the 2.4 mg / kg treated group over a wide intensity range: 0.1–2.1 log cd.s / m2 (p<0.001, Figure 1D).

[0190] By 2 weeks after treatment, all three doses of oral tonabersat hemichannel blocker resulted in significant recovery in mixed a-wave amplitude at intensities of 0.1 to 2.1 log cd.s / m² (p<0.001, Figure 1B-D). These animals had an improvement of approximately 500 µV at the maximal intensity employed in the ERG a-wave over the vehicle-treated light-injured group (p<0.001, Figure 1B-D). Treatment resulted in recovery of ERG function only slightly below the average of approximately -600 µV in SD rats. In other words, all three doses of hemichannel blocker restored ERG function.

[0191] For the 0.26 and 0.8 mg / kg tonabersat treatment groups, there was a significant improvement in mixed b-wave function 24 hours after treatment (Figure 1E-F), but not for the higher-dose treatment group (Figure 1G). However, a clear improvement in inner retinal function was observed for all three doses of tonabersat, as evidenced by increased mixed b-wave amplitude across all stimulus intensities by 1 and 2 weeks after treatment (Figure 1E-G). At the highest dose of tonabersat, 2.4 The 0.26 and 0.8 mg / kg doses showed the greatest improvement (average 1200 μV), which is within the normal range for absolute b-wave amplitude in uninjured SD rats.

[36] At 0.26 and 0.8 mg / kg, there was an improvement in absolute b-wave amplitude (average 1000 μV). Nevertheless, at the end of the 2-week recovery period, the mixed a-wave and mixed b-wave function of all tonabersat-treated animals was within the variance of normal uninjured albino rats. Heiduschka P, Schraermeyer U., Comparison of visual function in pigmented and albino rats by electroretinography and visual evoked potentials. Graefes Arch Clin Exp Ophthalmol. 2008;246:1559-73. In other words, all three doses of the hemichannel blocker restored inner retinal function.

[0192] A cohort of four animals treated with the maximum dose of oral tonabelsat (2.4 mg / kg) was maintained for three months under normal breeding and feeding conditions. The benefits of oral tonabelsat treatment were maintained long-term. ERG a-wave and b-wave amplitudes in the original seven treated animals assessed two weeks after oral tonabelsat (2.4 mg / kg) administration were only slightly lower compared with the cohort of four treated animals collected and assessed three months after oral tonabelsat administration. Compared to vehicle-treated controls, there was an improvement in photoreceptor function of over 400 μV in the a-wave and over 800 μV in the b-wave (Figure 2A-B). There was no change in PIII and PII rod responses three months after oral tonabelsat treatment compared to pre-light injury, suggesting that tonabelsat treatment fully preserved photoreceptor function. In contrast, in the vehicle-treated light-injured group, the changes in rod PIII and rod PII amplitude were significantly reduced at 3 months (p<0.001, Figure 2C-D). In other words, all three doses of hemichannel blockers restored photoreceptor function and PIII and PII rod responses.

[0193] Analysis of retinal layer and choroidal thickness was performed using optical coherence tomography (OCT) scans at 24 hours, 1 week, and 2 weeks after injury. Figure 3 shows typical fundus and OCT scan appearances 2 weeks after light injury for normal adult Sprague-Dawley rats, vehicle-treated light-injured rats, and 2.4 mg / kg tonabersat-treated animals (Figures 3A-C). Compared with the same eyes before light injury, significant thinning of both the retina and choroid was evident in vehicle-treated animals at 2 weeks (p<0.001; Figures 3A-B). The loss of retinal thickness was primarily due to thinning of the ONL. However, all three doses of oral tonabersat significantly preserved both retinal and choroidal thickness, and no thinning was detected at any of the posttreatment time points examined (24 hours, 1 week, and 2 weeks) (Figures 3D-F). Optical computed tomography (OCT) analysis 3 months after oral administration of 2.4 mg / kg tonabelsat showed that both retinal and choroidal thicknesses were significantly preserved compared to the vehicle-treated group (p<0.001, Figure 4A-B). Retinal thinning was evident in both the inner nuclear layer (INL; Figure 4C) and ONL layers (Figure 4D) in vehicle-treated animals, but there was no difference in ONL thickness in oral tonabelsat-treated animals compared to the same animals before the light damage procedure. At 3 months, there was a slight decrease in INL thickness in the oral tonabelsat-treated group compared to the same animals photographed before the light damage procedure (p<0.05). Vehicle-treated rats showed significant INL thinning compared to the same retinas before the light damage procedure (p<0.001). There was no difference in choroidal thickness between oral tonabelsat-treated rats at 3 months and the same rats evaluated before the light damage procedure (Figure 4E). In contrast, vehicle-treated light-injured rats evaluated at 3 months post-injury had significant choroidal thinning (p<0.001). In other words, all three doses of hemichannel blockers restored both retinal and choroidal structure.

[0194] After the final ERG and OCT assessments, the eyes were removed, and the posterior segment of the eye, including the retina and attached RPE-choroid-sclera, was evaluated using immunohistochemical labeling of GFAP, Iba-1 to determine the degree of gliosis (astrocytosis), and connexin 43 to determine microglial immunoreactivity before and after treatment. Compared to vehicle-treated rats (Figure 5A), tonabersat-treated rats had lower connexin 43 immunoreactivity in the retina at all three tonabersat doses used (Figure 5B-D). Iba-1 immunolabeled cells were less active in the inner plexiform layer (IPL) of the retina in drug-treated groups (Figure 5F-H) compared to vehicle-treated groups (Figure 5E). Slightly higher levels of Iba-1 reactivity were observed in 0.26 mg / kg-treated rats. GFAP immunoreactivity was not increased in the retinas of 0.8 mg / ml tonabelsat (Figure 5K) and 2.4 mg / kg tonabelsat (Figure 5L) compared with vehicle-treated rats (Figure 5I). There was a slight increase in GFAP labeling in animals receiving 0.26 mg / kg tonabelsat (Figure 5J), but it was significantly lower than that seen in vehicle-treated rats. Image quantitation showed significantly lower GFAP, connexin 43, and Iba-1 levels in all tonabelsat-treated groups compared with vehicle controls, with a dose-response trend (p<0.001) (Figure 6A-C) (higher doses were more effective in maintaining normal levels of these retinal inflammatory markers).

[0195] Example 3 Treatment with hemichannel blockers restored retinal function in hyperglycemic animals with diabetic retinopathy The mean body weights of control SD rats were 185 ± 1.1 g at 4 weeks of age, 198.2 ± 0.8 g at 6 weeks of age, and 217.5 ± 1.3 g at 8 weeks of age. Hyperglycemic rats weighed less: 172.5 ± 2.5 g at 4 weeks of age, 179.6 ± 2.1 g at 6 weeks of age, and 183.1 ± 1.8 g at 8 weeks of age. Differences between all three age groups and age-matched normal SD rats were statistically significant (t-test, p < 0.001). Blood glucose levels in normal SD rats ranged from 4.9 to 7.4 mmol / L (mean 6.07 mmol / L, no significant differences among age groups). In hyperglycemic rats, glucose levels ranged from 14.0 to 21.0 mmol / L, with means of 16.85 ± 0.63 mmol / L at 4 weeks, 15.43 ± 0.79 mmol / L at 6 weeks, and 16.54 ± 0.65 mmol / L at 8 weeks, demonstrating consistent levels of hyperglycemia from a young age. Differences between all three age groups of hyperglycemic rats and normal SD rats were statistically significant (t-test, p < 0.001).

[0196] Slit-lamp examination of the anterior segment (cornea, lens) of 4-week-old hyperglycemic rats revealed no obvious macroscopic differences compared with the SD rats from which this strain was derived. The cornea, lens, and iris appeared identical to those of normal SD rats, with no signs of diabetic cataract or neovascularization. However, optical coherence tomography (OCT) of hyperglycemic rats revealed an average of 5–8 hyperreflective spots per eye (based on seven evenly spaced OCT scans across the retina, thus resulting in an underestimate of the entire eye), compared with 1–2 or fewer in normal SD rats. The hyperreflective spots appeared to represent microaneurysms (20–30 μm in diameter) and giant aneurysms (140–160 μm) (Figure 7B–C), which were particularly located in the INL and ONL. There were no significant changes in retinal or choroidal thickness, although the choroid appeared to be slightly thinner in animals with aneurysms. Evans blue dye perfusion confirmed vascular leakage at the site of the aneurysm, which was mapped using OCT ( Fig. 7F ).

[0197] To determine whether the aneurysm affected retinal function, ERG analysis was performed at 5 weeks of age to compare the retinal function of hyperglycemic rats with that of normal SD rats. Representative ERG waveforms are shown in Figure 8. The mean mixed a-wave amplitude was significantly reduced in hyperglycemic rats compared with normal SD rats for intensities of 0.1 to 2.1 log cd.s / m² (p < 0.05). 0.01). At maximum intensity, SD rats measured -630 μV compared with -370 μV in the retinas of hyperglycemic diabetic rats. Mixed ERG b-wave amplitudes for intensities between -3.9 and 2.1 log cd.s / m2 were also significantly reduced in hyperglycemic rats (p<0.001). Normal SD rats exhibited a maximum intensity of 800 μV, whereas diabetic animals exhibited only 400 μV. There were no differences between a- and b-wave latencies. Further analysis revealed significantly reduced amplitudes in hyperglycemic rats for rod PIII (p<0.001), PII (p<0.001), and cone PII (p<0.001) responses, as well as for the total amplitude of the pulsating potential (OP) (p<0.001) (Fig. 8). There were no significant changes in rod PIII sensitivity or rod PII, cone PII, and OP total latencies.

[0198] For the tonabersat DR treatment group, 10 hyperglycemic rats grown to 5 weeks of age were divided equally into two groups. One group received a low dose of tonabersat at 0.28 mg / kg once daily for 14 days from weeks 5 to 7. At week 8, there was no difference in body weight between treated and untreated hyperglycemic rats, and there was no significant difference in retinal layer thickness (INL or ONL) or choroidal thickness. However, there was a difference in the number and size of microaneurysms after treatment (Figure 9A-B). Retinal function was significantly restored in drug-treated hyperglycemic rats compared with vehicle-injected hyperglycemic rats (Figure 9C). In treated animals, the mixed ERG a-wave was significantly higher (p<0.001) at intensities between 0.1 and 2.1 cd.s / m², with a maximum intensity of -630 µV compared with -370 µV in untreated animals at 8 weeks of age, approximately matching the levels in uninjured control Sprague-Dawley rats (Figure 8A). Similarly, the mixed b-wave signal was significantly restored in tonabersat-treated animals at all intensities (p<0.001). At this time point, the maximum intensity was 700 µV compared with only 400 µV in untreated controls (Figure 9D), again approximately returning to the mixed b-wave values ​​of normal Sprague-Dawley rats (see Figure 9B). Latencies were not different. Further analysis revealed that hyperglycemic rats treated with hemichannel blocker compounds significantly recovered rod PIII (p<0.001), PII (p<0.001), cone PII (p<0.01), and total OP (p<0.01) amplitudes (Figure 9E-H). There was no difference in latency before and after treatment. In other words, hemichannel blockers restored and restored retinal function and structure.

[0199] To determine whether the differences seen in OCT and ERG in hyperglycemic rats correlated with retinal inflammation, eyes were harvested at 8 weeks and subjected to immunohistochemistry. GFAP labeling was intense in the retinal ganglion cell (RGC) layer, and gliosis was observed in the area surrounding microaneurysms in the hyperglycemic rat retina, extending from the nerve fiber layer (FLL) to the ONL, suggesting Müller cell activation (Figure 10A). Hyperglycemic retinas had abnormally high Iba-1 labeling (Figure 10B), suggesting activated microglia in the inner retinal layer, where cells with swollen cell bodies and numerous elongated branches were present. Connexin 43 labeling was abnormally high in the GCL of hyperglycemic rats (Figure 10C). Hyperglycemic rats administered tonabersat daily for 14 days had reduced inflammation, as evidenced by reduced labeling for all three markers (Figure 10E-F). Quantification of the results is shown in Figure 10G, which shows that all three markers, GFAP, connexin 43, and Iba-1, were significantly higher in untreated hyperglycemic rats compared to uninjured control retinas (p<0.001), and at 8 weeks of age, all three treatment groups had returned to normal, showing significantly lower labeling than levels in untreated rat retinas (p<0.001). * * *

[0200] The invention described and claimed herein has many features and embodiments, including but not limited to those described or referenced in the detailed disclosure. It is not intended to be all-inclusive, and the invention described and claimed herein may be The present invention is not limited to the features or embodiments specified in the detailed disclosure section, which are included for illustrative purposes only and are not limiting. Those skilled in the art will readily recognize that many of the components and parameters can be changed or modified to a certain extent or substituted with known equivalents without departing from the scope of the present invention. It should be recognized that such modifications and equivalents are incorporated herein as if individually set forth. The present invention also includes all of the steps, properties, compositions, and compounds referred to or shown in this specification, individually or collectively, as well as any and all combinations of any two or more of the foregoing steps or properties.

[0201] All patents, publications, scientific papers, websites, and other documents and materials referenced or mentioned herein are indicative of the level of skill of those skilled in the art to which the present invention pertains, and each such referenced document and material is incorporated by reference herein to the same extent as if individually incorporated by reference in its entirety or as if set forth in its entirety herein. Applicant reserves the right to physically incorporate into this specification all materials and information from any such patents, publications, scientific papers, websites, electronically available information, and other referenced materials or documents. Reference herein to any applications, patents, and publications is not, and should not be taken as, an acknowledgment or any form of suggestion that they constitute valid prior art or form part of the universal general knowledge of any country in the world.

[0202] The specific methods and compositions described herein are representative of preferred embodiments and are exemplary and are not intended as limitations on the scope of the invention. Other objects, aspects, and embodiments will occur to those skilled in the art upon consideration of this specification and are encompassed within the spirit of the invention as defined by the claims. It will be readily apparent to those skilled in the art that various substitutions and modifications can be made to the invention disclosed herein without departing from the scope and spirit of the invention. The invention illustratively described herein may suitably be practiced in the absence of any element or limitation not specifically disclosed herein as essential. Thus, for example, in each example and embodiment or example of the invention herein, any of the terms "comprising," "consisting essentially of," and "consisting of" may be replaced with either of the other two terms herein. The methods and processes illustratively described herein may be performed in a different order of steps and are not necessarily limited to the order of steps set forth in the specification or claims. Also, as used in this specification and the appended claims, the singular forms (a, an, and the) include plural referents unless the context clearly indicates otherwise. Under no circumstances shall the patent be construed as limited to the particular examples or embodiments or methods specifically disclosed herein. Under no circumstances shall the patent be construed as limited by statements by an examiner or any other Patent and Trademark Office officer or employee, unless such statements are specific and absent requirements or reservations expressly adopted in the applicant's written response. Furthermore, titles, headings, and the like are provided to enhance the reader's comprehension of this document and should not be read as limiting the scope of the invention. Any examples of aspects, embodiments, or components of the invention referenced herein shall be considered non-limiting.

[0203] The terms and expressions employed are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions to exclude any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention as claimed. Thus, while the invention has been specifically disclosed by preferred embodiments and optional features, it will be understood that modifications and variations of the concepts of this disclosure may be reclassified by those skilled in the art, and that such modifications and variations are deemed to be within the scope of the invention as defined by the appended claims.

[0204] The invention is described broadly and generically herein. Each of the narrower species and subgeneric groupings included in the generic disclosure also form part of the invention. This includes generic descriptions of the invention with provisos or negative limitations removing any subject matter from the genus, regardless of whether the excluded material is specifically recited herein.

[0205] Other embodiments are within the scope of the following claims. Furthermore, when features or aspects of the invention are described in terms of Markush groups, one of ordinary skill in the art will thereby recognize that the invention is also described with respect to any individual member or subgroup of members of the Markush group. The present invention provides, for example, the following items. (Item 1) 1. A method for restoring or restoring retinal function in a subject having a chronic retinal disorder, comprising administering to the subject an effective amount of a hemichannel blocker. (Item 2) 1. A method for restoring or restoring retinal structure in a subject having a chronic retinal disorder, comprising administering to the subject an effective amount of a hemichannel blocker. (Item 3) 1. A method for restoring or restoring choroidal function in a subject with a chronic retinal disorder, comprising administering to the subject an effective amount of a hemichannel blocker. (Item 4) 1. A method for restoring or restoring choroidal structure in a subject with a chronic retinal disorder, comprising administering to the subject an effective amount of a hemichannel blocker. (Item 5) 5. The method according to any one of items 1 to 3 or 4, wherein the hemichannel blocker is a connexin 43 hemichannel blocker. (Item 6) 5. The method according to any one of items 1 to 3 or 4, wherein the hemichannel blocker is a small molecule hemichannel blocker. (Item 7) 5. The method according to any one of items 1 to 3 or 4, wherein the hemichannel blocker is N-[(3S,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]-3-chloro-4-fluorobenzamide (tonabersat). (Item 8) The small molecule hemichannel blocker is a small molecule hemichannel blocker of formula (I) or (II): [ka] wherein Y is C-R1; R1 is acetyl; R2 is hydrogen, C 3-8 Cycloalkyl, optionally interrupted by oxygen, or hydroxy, C 1-6 C substituted by alkoxy or substituted aminocarbonyl 1-6 Alkyl, C 1-6 Alkyl carbonyl, C 1-6 Alkoxycarbonyl, C 1-6 Alkylcarbonyloxy, C 1-6 alkoxy, nitro, cyano, halo, trifluoromethyl, or CF3S; or a CF3-A- group, where A is -CF2-, -CO-, -CH2-, CH(OH), SO2, SO, CH2-O, or CONH; or a CF2H-A'- group, where A' is oxygen, sulfur, SO, SO2, CF2, or CFH; trifluoromethoxy, C 1-6Alkyl sulfinyl, perfluoro C 2-6 Alkylsulfonyl, C 1-6 Alkylsulfonyl, C 1-6 Al Coxysulfinyl, C 1-6 Alkoxysulfonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulfinyl, heteroarylsulfinyl, arylsulfonyl, or heteroarylsulfonyl optionally substituted on any aromatic moiety, C 1-6 Alkylcarbonylamino, C 1-6 Alkoxycarbonylamino, C 1-6 Alkyl-thiocarbonyl, C 1-6 Alkoxy-thiocarbonyl, C 1-6 Alkyl-thiocarbonyloxy, 1-mercapto C 2-7 alkyl, formyl, or any amino moiety optionally containing one or two C 1-6 Alkyl group, or C 1-6 Alkylsulfinylamino, C 1-6 Alkyl sulfonyl amino, C 1-6 Alkoxysulfinylamino or C 1-6 substituted with alkoxysulfonylamino, or C 1-6 alkylcarbonyl, aminosulfinyl, aminosulfonyl or aminocarbonyl substituted with ethylenyl termini by nitro or cyano, or -C(C 1-6 alkyl)NOH or -C(C 1-6 alkyl)NNH; or one or two C 1-6 optionally substituted with alkyl, or C 2-7 amino optionally substituted with alkanoyl; one of R and R is hydrogen or C 1-4 alkyl, and the other is C 1-4 Alkyl, CF3 or CH2X a are fluoro, chloro, bromo, iodo, C 1-4 Alkoxy, hydroxy, C 1-4 Alkylcarbonyloxy, -SC1-4 Alkyl, nitro, optionally one or two C 1-4 Amino, cyano, or C substituted with alkyl groups 1-4 or R3 and R4 together are C 1-4 C optionally substituted with alkyl 2-5 Polymethylene; R5 is C 1-6 Alkylcarbonyloxy, benzoyloxy, ONO2, benzyloxy, phenyloxy, or C 1-6 alkoxy, and R6 and R9 are hydrogen, or R5 is hydroxy, and R6 is hydrogen or C 1-2 alkyl, and R9 is hydrogen; R7 is heteroaryl or phenyl, both of which are independently and optionally substituted one or more times with groups or atoms selected from chloro, fluoro, bromo, iodo, nitro, amino, where amino is C 1-4 Alkyl, cyano, azido, C 1-4 optionally substituted once or twice with alkoxy, trifluoromethoxy, and trifluoromethyl; R8 is hydrogen, C 1-6 Alkyl, OR 11 or NHCOR 10 where R 11 is hydrogen, C 1-6 Alkyl, formyl, C 1-6 Alkanoyl, aroyl or aryl-C 1-6 alkyl, and R 10 is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, mono or di C 1-6 Alkylamino, Amino-C 1-6 Alkyl, Hydroxy-C 1-6 Alkyl, Halo-C 1-6 Alkyl, C 1-6 Acyloxy-C 1-6 Alkyl, C 1-6 Alkoxycarbonyl-C 1-6-alkyl, aryl, or heteroaryl; the R8-N-CO-R7 group is cis to the R5 group; and X is oxygen or NR 12 where R 12 is hydrogen or C 1-6 is alkyl; or Formula II [ka] During the ceremony, Q is O or the formula =NHOR 43 where R 43 teeth, (i) H, C 1-4 fluoroalkyl, or optionally substituted C 1-4 alkyl, or (ii)-A 300 -R 300 wherein A 300 is a direct bond, -C(O)O*-, -C(R3)(R4)O*-, -C(O)OC(R3)(R4)O*- or -C(R3)(R4)OC(O)O*-, where the atom marked with * is 300 R3 and R4 are independently selected from H, Fluoro, and C. 1-4 Alkyl, or C 1-4 fluoroalkyl, or R3 and R4 together with the atom to which they are attached form a cyclopropyl group, and R 300 is selected from the group [1], [2], [2A], [3], [4], [5] or [6]; R2 is H, A is a direct bond, -C(O)O*-, -C(R3)(R4)O*-, -C(O)OC(R3)(R4)O*-, or -C(R3)(R4)OC(O)O*-, where the atom marked with * is directly connected to R1, and R3 and R4 are independently H, fluoro, C 1-4 Alkyl, or C 1-4 fluoroalkyl, or R3 and R4 together with the atom to which they are attached form a cyclopropyl group; R1 is selected from the group [1], [2], [2A], [3], [4], [5] and [6], and atoms marked with ** are directly connected to A; [ka] R5 and R6 are independently H, C 1-4 Alkyl, C 1-4 fluoroalkyl, and benzyl; R7 is independently H, C 1-4 Alkyl, and C 1-4 fluoroalkyl; The R8 is (i) H, C 1-4 Alkyl or C 1-4 fluoroalkyl, or (ii) the side chain of a natural or unnatural alpha-amino acid or peptide described herein; or (iii) biotin or chemically linked to biotin; R9 is H, -N(R 11 )(R 12 ), or -N + (R 11 )(R 12 )(R 13 )X - , or -N(R 11 )C(O)R 14 is selected from In the formula, R 11 , R 12 , and R 13 are independently H, C 1-4 Alkyl, or C 1-4 fluoroalkyl; R 14 is H, C 1-4 Alkyl, or C 1-4 is a fluoroalkyl; R 15 independently, C 1-4 Alkyl and C 1-4 fluoroalkyl, and X -7. The method of claim 6, wherein is a pharmaceutically acceptable anion. (Item 9) 5. The method according to any one of items 1 to 3 or 4, wherein the hemichannel blocker is orally administered in an amount ranging from about 10 to 200 mg per day. (Item 10) 8. The method according to item 7, wherein the hemichannel blocker is orally administered in an amount ranging from about 10 to about 200 mg per day. (Item 11) 8. The method according to item 7, wherein the hemichannel blocker is orally administered in an amount ranging from about 0.2 mg / kg to about 5 mg / kg. (Item 12) 8. The method of claim 7, wherein the circulating concentration of tonabersat in the subject is in the range of about 10 micromolar to about 90 micromolar. (Item 13) Item 10. The method of item 1, wherein the hemichannel blocker is administered by injection. (Item 14) 2. The method of claim 1, wherein the hemichannel blocker is administered orally. (Item 15) 5. The method according to items 1 to 3 or 4, wherein the hemichannel blocker is administered once a day. (Item 16) 5. The method according to items 1 to 3 or 4, wherein the hemichannel blocker is administered once a week. (Item 17) 8. The method of claim 7, wherein the subject is a human. (Item 18) Item 10. The method of claim 1, wherein the hemichannel blocker is not in a composition comprising microparticles. (Item 19) 2. The method of claim 1, wherein the retinal function is selected from mixed a-wave function, mixed b-wave function, and / or PII and PIII rod and cone function. (Item 20) 1. A method of improving retinal structural integrity in a subject with a chronic retinal disorder, comprising administering to the subject an effective amount of a hemichannel blocker. (Item 21) 21. The method of item 20, wherein the retinal pigment epithelium is restored. (Item 22) 21. The method of item 20, wherein the retinal vascular endothelium is restored. (Item 23) 21. The method of item 20, wherein normal retinal layer structure is restored. (Item 24) A method for reducing or eliminating microaneurysms and / or giant aneurysms in a subject with a chronic retinal disorder, comprising administering to the subject an effective amount of a hemichannel blocker. (Item 25) 1. A method of improving photoreceptor function in a subject with a chronic retinal disorder, comprising administering to the subject an effective amount of a hemichannel blocker. (Item 26) 1. A method of improving choroidal structural integrity in a subject with a chronic retinal disorder, comprising administering to the subject an effective amount of a hemichannel blocker. (Item 27) 27. The method of claim 26, wherein choroidal thickness is restored. (Item 28) 27. The method of item 26, wherein the choroidal vascular bed is restored. (Item 29) 1. A method for improving choroidal vascular blood flow to the outer retina in a subject with a chronic retinal disorder, comprising administering to the subject an effective amount of a hemichannel blocker. (Item 30) 1. A method of improving choroidal blood flow in a subject with a chronic retinal disorder, comprising administering to the subject an effective amount of a hemichannel blocker. (Item 31) 1. A method of increasing the survival of retinal function in a subject in need thereof, comprising administering to the subject a survival-promoting amount of N-[(3S,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]-3-chloro-4-fluorobenzamide (Xiflam). (Item 32) Item 32. The method according to Item 31, wherein the retention-promoting amount is 10 to 200 mg per day. (Item 33) Item 32. The method according to Item 31, wherein the retention-promoting amount is 20 to 100 mg per day. (Item 34) 32. The method of claim 31, wherein said increased survival treats a chronic retinal disorder. (Item 35) Item 35. The method of item 34, wherein the chronic retinal disorder is diabetic retinopathy. (Item 36) 35. The method of claim 34, wherein the chronic retinal disorder is diabetic macular edema. (Item 37) 35. The method of claim 34, wherein the chronic retinal disorder is selected from the group consisting of wet age-related macular degeneration, dry age-related macular degeneration, geographic atrophy, and hypertensive retinopathy. (Item 38) Item 35. The method according to item 34, wherein the chronic retinal disorder is caused by retinal degeneration, edema, diabetes, ischemic retinal degeneration, retinal vascular occlusion, and central retinal vein occlusion. (Item 39) 32. The method of claim 31, wherein mixed a-wave function and / or improved mixed b-wave function is improved. (Item 40) The method according to item 31, wherein the function of PII and PIII rods and cones is improved. (Item 41) 32. The method of item 31, wherein ERG function is improved. (Item 42) 32. The method of item 31, wherein inner retinal function is improved. (Item 43) 32. The method of claim 31, wherein photoreceptor function is improved. (Item 44) 1. A method of increasing survival of retinal structures in a subject in need thereof, comprising administering to the subject 10 to 200 mg per day of N-[(3S,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]-3-chloro-4-fluorobenzamide (Xiflam). (Item 45) 45. The method of claim 44, wherein the retinal structure comprises the retinal pigment epithelium, the retinal vascular endothelium, and / or a structure of a retinal layer. (Item 46) 45. The method of claim 44, wherein microaneurysms and / or giant aneurysms in the retina are reduced. (Item 47) 1. A method of increasing residual choroidal function in a subject in need thereof, comprising administering to the subject 10 to 200 mg per day of N-[(3S,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]-3-chloro-4-fluorobenzamide (Xiflam). (Item 48) Item 48. The method according to item 47, wherein choroidal blood flow is improved. (Item 49) 48. The method of item 47, wherein blood flow in the choroidal vessels supplying the outer retina is improved. (Item 50) Item 48. The method according to item 47, wherein regulation of choroidal blood flow is improved. (Item 51) 1. A method of increasing choroidal structure survival in a subject in need thereof, comprising administering to the subject 10 to 200 mg per day of N-[(3S,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]-3-chloro-4-fluorobenzamide (Xiflam). (Item 52) Item 52. The method of item 51, wherein choroidal thickness is improved. (Item 53) 52. The method of claim 51, wherein the choroidal vascular bed is improved. (Item 54) 32. The method of claim 31, wherein the increased residual retinal function recovers or restores retinal function. (Item 55) 45. The method of item 44, wherein increasing survival of retinal structures restores or restores retinal structures. (Item 56) Item 48. The method of item 47, wherein the increased residual choroidal function restores or restores choroidal function. (Item 57) 52. The method of claim 51, wherein increasing the survival of choroidal structures restores or restores choroidal structures.

Claims

1. A composition comprising a hemichannel blocker for use in a method for restoring or recovering retinal function in a subject having a chronic retinal disorder selected from the group consisting of diabetic retinopathy, nonproliferative diabetic retinopathy, diabetic macular edema, inflammatory or infectious choroiditis, and uveitis, wherein the hemichannel blocker is N-[(3S,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]-3-chloro-4-fluorobenzamide (tonabelsat), or a hemichannel blocker of the following formula (I) or formula (II): 【Transformation 8】 In the formula, Y is C-R 1; R1 is acetyl; R2 is hydrogen, C3-8 cycloalkyl, optionally interrupted by oxygen, or substituted with hydroxy, C1-6 alkoxy or substituted aminocarbonyl C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyloxy, C1-6 alkoxy, nitro, cyano, halo, trifluoromethyl, or CF3S; or CF3-A-group, where A is -CF2-, -CO-, -CH2-, CH(OH), SO2, SO, CH2-O, or CONH; or CF2H-A'-group, where A' is oxygen, sulfur, SO, SO2, CF2, or CFH; trifluoromethoxy, C1-6 alkylsulfinyl, perfluoroC2-6 Alkylsulfonyl, C1-6 alkylsulfonyl, C1-6 alkoxysulfinyl, C1-6 alkoxysulfonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulfinyl, heteroarylsulfinyl, arylsulfonyl, or heteroarylsulfonyl (any aromatic part is optionally substituted), C1-6 alkylcarbonylamino, C1-6 alkoxycarbonylamino, C1-6 alkyl-thiocarbonyl, C1-6 alkoxy-thiocarbonyl, C1-6 alkyl-thiocarbonyloxy, 1-mercaptoC2-7 alkyl, formyl, or aminosulfinyl, aminosulfonyl or aminocarbonyl where any amino part is optionally substituted with one or two C1-6 alkyl groups, or C1-6 alkylsulfinylamino, C1-6 alkylsulfonylamino, C1-6 It is an alkoxysulfinylamino or C1-6 alkoxysulfonylamino, or an ethilenyl terminally substituted with a C1-6 alkylcarbonyl, nitro or cyano, or -C(C1-6 alkyl)NOH or -C(C1-6 alkyl)NNH2;or an amino that is optionally substituted with one or two C1-6 alkyl groups, or optionally substituted with a C2-7 alkanoyl group; One of R3 and R4 is hydrogen or a C1-4 alkyl group, and the other is a C1-4 alkyl group, CF3 or CH2Xa is a fluoro, chloro, bromo, iodo, C1-4 alkoxy, hydroxy, C1-4 alkylcarbonyloxy, -S-C1-4 alkyl, nitro, an amino, cyano, or C1-4 alkoxycarbonyl group optionally substituted with one or two C1-4 alkyl groups; or R3 and R4 are both C2-5 polymethylene groups optionally substituted with C1-4 alkyl groups; R5 is a C1-6 alkylcarbonyloxy, benzoyloxy, ONO2, benzyloxy, phenyloxy, or C1-6 alkoxy, and R6 and R9 are hydrogen, or R5 is hydroxyl, R6 is hydrogen or a C1-2 alkyl, and R9 is hydrogen; R7 is a heteroaryl or phenyl group, both of which are independently and optionally substituted once or twice with a group or atom selected from chloro, fluoro, bromo, iodo, nitro, or amino, in which case the amino group is optionally substituted once or twice with C1-4 alkyl, cyano, azide, C1-4 alkoxy, trifluoromethoxy, and trifluoromethyl groups; R8 is hydrogen, C1-6 alkyl, OR11 or NHCOR10, where R11 is hydrogen, C1-6 alkyl, formyl, C1-6 alkanoyl, aroyl or aryl-C1-6 alkyl; R10 is hydrogen, C1-6 alkyl, C1-6 alkoxy, mono or di-C1-6 alkylamino, amino-C1-6 alkyl, hydroxy-C1-6 alkyl, halo-C1-6 alkyl, C1-6 acyloxy-C1-6 alkyl, C1-6 alkoxycarbonyl-C1-6 alkyl, aryl or heteroaryl; the R8-N-CO-R7 group is cis relative to the R5 group; and X is oxygen or NR12, where R12 is hydrogen or C 1-6 alkyl; or formula II 【Chemistry 9】 During the ceremony, Q is O or the oxime of formula = NOR 43, where R 43 is (i) Selected from H, C1-4 fluoroalkyl, or optionally substituted C1-4 alkyl, (ii) -A 300 -R 300, where A 300 is directly bonded, -C(O)O*-, -C(R 3)(R 4)O*-, -C(O)O-C(R 3)(R 4)O*-, or -C(R 3)(R 4)OC(O)O*-, where the atom marked with * is directly bonded to R 300, R 3 and R 4 are independently selected from H, fluoro, C1-4 alkyl, or C1-4 fluoroalkyl, or R 3 and R 4 form a cyclopropyl group with the atom to which they are bonded, and R 300 is selected from the group [1], [2], [2A], [3], [4], [5] or [6]; R2 is H, A is directly bonded, -C(O)O*-, -C(R3)(R4)O*-, -C(O)O-C(R3)(R4)O*-, or -C(R3)(R4)OC(O)O*-, where the atom marked with * is directly bonded to R1, R3 and R4 are independently selected from H, fluoro, C1-4 alkyl, or C1-4 fluoroalkyl, or R3 and R4 together with the atom to which they are bonded form a cyclopropyl group. R1 is selected from the groups [1], [2], [2A], [3], [4], [5] and [6], and atoms marked with ** are directly attached to A. 【Chemistry 10】 R5 and R6 are independently selected from H, C1-4 alkyl, C1-4 fluoroalkyl, and benzyl; R7 is independently selected from H, C1-4 alkyl, and C1-4 fluoroalkyl; R 8 is, (i) H, C1-4 alkyl or C1-4 fluoroalkyl, or (ii) Side chains of natural or unnatural alpha-amino acids, (iii) Biotin, or a biotin-chemically linked substance Selected from; R9 is selected from H, -N(R11)(R12), or -N+(R11)(R12)(R13)X-, or -N(R11)C(O)R14. In the formula, R11, R12, and R13 are independently selected from H, C1-4 alkyl, or C1-4 fluoroalkyl. R14 is H, C1-4 alkyl, or C1-4 fluoroalkyl, R 15 is independently selected from C1-4 alkyl and C1-4 fluoroalkyl, and X- is a pharmaceutically acceptable anion. composition.

2. A composition comprising a hemichannel blocker for use in a method of restoring or resuscitating retinal structure in a subject having a chronic retinal disorder selected from the group consisting of diabetic retinopathy, nonproliferative diabetic retinopathy, diabetic macular edema, inflammatory or infectious choroiditis, and uveitis, wherein the hemichannel blocker is N-[(3S,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]-3-chloro-4-fluorobenzamide (tonabelsat), or a hemichannel blocker of the following formula (I) or formula (II): 【Transformation 8】 In the formula, Y is C-R 1; R1 is acetyl; R2 is hydrogen, C3-8 cycloalkyl, optionally interrupted by oxygen, or substituted with hydroxy, C1-6 alkoxy or substituted aminocarbonyl C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyloxy, C1-6 alkoxy, nitro, cyano, halo, trifluoromethyl, or CF3S; or CF3-A-group, where A is -CF2-, -CO-, -CH2-, CH(OH), SO2, SO, CH2-O, or CONH; or CF2H-A'-group, where A' is oxygen, sulfur, SO, SO2, CF2, or CFH; trifluoromethoxy, C1-6 alkylsulfinyl, perfluoroC2-6 Alkylsulfonyl, C1-6 alkylsulfonyl, C1-6 alkoxysulfinyl, C1-6 alkoxysulfonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulfinyl, heteroarylsulfinyl, arylsulfonyl, or heteroarylsulfonyl (any aromatic part is optionally substituted), C1-6 alkylcarbonylamino, C1-6 alkoxycarbonylamino, C1-6 alkyl-thiocarbonyl, C1-6 alkoxy-thiocarbonyl, C1-6 alkyl-thiocarbonyloxy, 1-mercaptoC2-7 alkyl, formyl, or aminosulfinyl, aminosulfonyl or aminocarbonyl where any amino part is optionally substituted with one or two C1-6 alkyl groups, or C1-6 alkylsulfinylamino, C1-6 alkylsulfonylamino, C1-6 It is an alkoxysulfinylamino or C1-6 alkoxysulfonylamino, or an ethilenyl terminally substituted with a C1-6 alkylcarbonyl, nitro or cyano, or -C(C1-6 alkyl)NOH or -C(C1-6 alkyl)NNH2;or an amino that is optionally substituted with one or two C1-6 alkyl groups, or optionally substituted with a C2-7 alkanoyl group; One of R3 and R4 is hydrogen or a C1-4 alkyl group, and the other is a C1-4 alkyl group, CF3 or CH2Xa is a fluoro, chloro, bromo, iodo, C1-4 alkoxy, hydroxy, C1-4 alkylcarbonyloxy, -S-C1-4 alkyl, nitro, an amino, cyano, or C1-4 alkoxycarbonyl group optionally substituted with one or two C1-4 alkyl groups; or R3 and R4 are both C2-5 polymethylene groups optionally substituted with C1-4 alkyl groups; R5 is a C1-6 alkylcarbonyloxy, benzoyloxy, ONO2, benzyloxy, phenyloxy, or C1-6 alkoxy, and R6 and R9 are hydrogen, or R5 is hydroxyl, R6 is hydrogen or a C1-2 alkyl, and R9 is hydrogen; R7 is a heteroaryl or phenyl group, both of which are independently and optionally substituted once or twice with a group or atom selected from chloro, fluoro, bromo, iodo, nitro, or amino, in which case the amino group is optionally substituted once or twice with C1-4 alkyl, cyano, azide, C1-4 alkoxy, trifluoromethoxy, and trifluoromethyl groups; R8 is hydrogen, C1-6 alkyl, OR11 or NHCOR10, where R11 is hydrogen, C1-6 alkyl, formyl, C1-6 alkanoyl, aroyl or aryl-C1-6 alkyl; R10 is hydrogen, C1-6 alkyl, C1-6 alkoxy, mono or di-C1-6 alkylamino, amino-C1-6 alkyl, hydroxy-C1-6 alkyl, halo-C1-6 alkyl, C1-6 acyloxy-C1-6 alkyl, C1-6 alkoxycarbonyl-C1-6 alkyl, aryl or heteroaryl; the R8-N-CO-R7 group is cis relative to the R5 group; and X is oxygen or NR12, where R12 is hydrogen or C 1-6 alkyl; or formula II 【Chemistry 9】 During the ceremony, Q is O or the oxime of formula = NOR 43, where R 43 is (i) Selected from H, C1-4 fluoroalkyl, or optionally substituted C1-4 alkyl, (ii) -A 300 -R 300, where A 300 is directly bonded, -C(O)O*-, -C(R 3)(R 4)O*-, -C(O)O-C(R 3)(R 4)O*-, or -C(R 3)(R 4)OC(O)O*-, where the atom marked with * is directly bonded to R 300, R 3 and R 4 are independently selected from H, fluoro, C1-4 alkyl, or C1-4 fluoroalkyl, or R 3 and R 4 form a cyclopropyl group with the atom to which they are bonded, and R 300 is selected from the group [1], [2], [2A], [3], [4], [5] or [6]; R2 is H, A is directly bonded, -C(O)O*-, -C(R3)(R4)O*-, -C(O)O-C(R3)(R4)O*-, or -C(R3)(R4)OC(O)O*-, where the atom marked with * is directly bonded to R1, R3 and R4 are independently selected from H, fluoro, C1-4 alkyl, or C1-4 fluoroalkyl, or R3 and R4 together with the atom to which they are bonded form a cyclopropyl group. R1 is selected from the groups [1], [2], [2A], [3], [4], [5] and [6], and atoms marked with ** are directly attached to A. 【Chemistry 10】 R5 and R6 are independently selected from H, C1-4 alkyl, C1-4 fluoroalkyl, and benzyl; R7 is independently selected from H, C1-4 alkyl, and C1-4 fluoroalkyl; R 8 is, (i) H, C1-4 alkyl or C1-4 fluoroalkyl, or (ii) Side chains of natural or unnatural alpha-amino acids, (iii) Biotin, or a biotin-chemically linked substance Selected from; R9 is selected from H, -N(R11)(R12), or -N+(R11)(R12)(R13)X-, or -N(R11)C(O)R14. In the formula, R11, R12, and R13 are independently selected from H, C1-4 alkyl, or C1-4 fluoroalkyl. R14 is H, C1-4 alkyl, or C1-4 fluoroalkyl, R 15 is independently selected from C1-4 alkyl and C1-4 fluoroalkyl, and X- is a pharmaceutically acceptable anion. composition.

3. A composition comprising a hemichannel blocker for use in a method for restoring or recovering choroidal function in a subject having a chronic retinal disorder selected from the group consisting of diabetic retinopathy, nonproliferative diabetic retinopathy, diabetic macular edema, inflammatory or infectious choroiditis, and uveitis, wherein the hemichannel blocker is N-[(3S,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]-3-chloro-4-fluorobenzamide (tonabelsat), or a hemichannel blocker of the following formula (I) or formula (II): 【Transformation 8】 In the formula, Y is C-R 1; R1 is acetyl; R2 is hydrogen, C3-8 cycloalkyl, optionally interrupted by oxygen, or substituted with hydroxy, C1-6 alkoxy or substituted aminocarbonyl C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyloxy, C1-6 alkoxy, nitro, cyano, halo, trifluoromethyl, or CF3S; or CF3-A-group, where A is -CF2-, -CO-, -CH2-, CH(OH), SO2, SO, CH2-O, or CONH; or CF2H-A'-group, where A' is oxygen, sulfur, SO, SO2, CF2, or CFH; trifluoromethoxy, C1-6 alkylsulfinyl, perfluoroC2-6 Alkylsulfonyl, C1-6 alkylsulfonyl, C1-6 alkoxysulfinyl, C1-6 alkoxysulfonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulfinyl, heteroarylsulfinyl, arylsulfonyl, or heteroarylsulfonyl (any aromatic part is optionally substituted), C1-6 alkylcarbonylamino, C1-6 alkoxycarbonylamino, C1-6 alkyl-thiocarbonyl, C1-6 alkoxy-thiocarbonyl, C1-6 alkyl-thiocarbonyloxy, 1-mercaptoC2-7 alkyl, formyl, or aminosulfinyl, aminosulfonyl or aminocarbonyl where any amino part is optionally substituted with one or two C1-6 alkyl groups, or C1-6 alkylsulfinylamino, C1-6 alkylsulfonylamino, C1-6 It is an alkoxysulfinylamino or C1-6 alkoxysulfonylamino, or an ethilenyl terminally substituted with a C1-6 alkylcarbonyl, nitro or cyano, or -C(C1-6 alkyl)NOH or -C(C1-6 alkyl)NNH2;or an amino that is optionally substituted with one or two C1-6 alkyl groups, or optionally substituted with a C2-7 alkanoyl group; One of R3 and R4 is hydrogen or a C1-4 alkyl group, and the other is a C1-4 alkyl group, CF3 or CH2Xa is a fluoro, chloro, bromo, iodo, C1-4 alkoxy, hydroxy, C1-4 alkylcarbonyloxy, -S-C1-4 alkyl, nitro, an amino, cyano, or C1-4 alkoxycarbonyl group optionally substituted with one or two C1-4 alkyl groups; or R3 and R4 are both C2-5 polymethylene groups optionally substituted with C1-4 alkyl groups; R5 is a C1-6 alkylcarbonyloxy, benzoyloxy, ONO2, benzyloxy, phenyloxy, or C1-6 alkoxy, and R6 and R9 are hydrogen, or R5 is hydroxyl, R6 is hydrogen or a C1-2 alkyl, and R9 is hydrogen; R7 is a heteroaryl or phenyl group, both of which are independently and optionally substituted once or twice with a group or atom selected from chloro, fluoro, bromo, iodo, nitro, or amino, in which case the amino group is optionally substituted once or twice with C1-4 alkyl, cyano, azide, C1-4 alkoxy, trifluoromethoxy, and trifluoromethyl groups; R8 is hydrogen, C1-6 alkyl, OR11 or NHCOR10, where R11 is hydrogen, C1-6 alkyl, formyl, C1-6 alkanoyl, aroyl or aryl-C1-6 alkyl; R10 is hydrogen, C1-6 alkyl, C1-6 alkoxy, mono or di-C1-6 alkylamino, amino-C1-6 alkyl, hydroxy-C1-6 alkyl, halo-C1-6 alkyl, C1-6 acyloxy-C1-6 alkyl, C1-6 alkoxycarbonyl-C1-6 alkyl, aryl or heteroaryl; the R8-N-CO-R7 group is cis relative to the R5 group; and X is oxygen or NR12, where R12 is hydrogen or C 1-6 alkyl; or formula II 【Chemistry 9】 During the ceremony, Q is O or the oxime of formula = NOR 43, where R 43 is (i) Selected from H, C1-4 fluoroalkyl, or optionally substituted C1-4 alkyl, (ii) -A 300 -R 300, where A 300 is directly bonded, -C(O)O*-, -C(R 3)(R 4)O*-, -C(O)O-C(R 3)(R 4)O*-, or -C(R 3)(R 4)OC(O)O*-, where the atom marked with * is directly bonded to R 300, R 3 and R 4 are independently selected from H, fluoro, C1-4 alkyl, or C1-4 fluoroalkyl, or R 3 and R 4 form a cyclopropyl group with the atom to which they are bonded, and R 300 is selected from the group [1], [2], [2A], [3], [4], [5] or [6]; R2 is H, A is directly bonded, -C(O)O*-, -C(R3)(R4)O*-, -C(O)O-C(R3)(R4)O*-, or -C(R3)(R4)OC(O)O*-, where the atom marked with * is directly bonded to R1, R3 and R4 are independently selected from H, fluoro, C1-4 alkyl, or C1-4 fluoroalkyl, or R3 and R4 together with the atom to which they are bonded form a cyclopropyl group. R1 is selected from the groups [1], [2], [2A], [3], [4], [5] and [6], and atoms marked with ** are directly attached to A. 【Chemistry 10】 R5 and R6 are independently selected from H, C1-4 alkyl, C1-4 fluoroalkyl, and benzyl; R7 is independently selected from H, C1-4 alkyl, and C1-4 fluoroalkyl; R 8 is, (i) H, C1-4 alkyl or C1-4 fluoroalkyl, or (ii) Side chains of natural or unnatural alpha-amino acids, (iii) Biotin, or a biotin-chemically linked substance Selected from; R9 is selected from H, -N(R11)(R12), or -N+(R11)(R12)(R13)X-, or -N(R11)C(O)R14. In the formula, R11, R12, and R13 are independently selected from H, C1-4 alkyl, or C1-4 fluoroalkyl. R14 is H, C1-4 alkyl, or C1-4 fluoroalkyl, R 15 is independently selected from C1-4 alkyl and C1-4 fluoroalkyl, and X- is a pharmaceutically acceptable anion. composition.

4. A composition comprising a hemichannel blocker for use in a method for restoring or resuscitating choroidal structure in a subject having a chronic retinal disorder selected from the group consisting of diabetic retinopathy, nonproliferative diabetic retinopathy, diabetic macular edema, inflammatory or infectious choroiditis, and uveitis, wherein the hemichannel blocker is N-[(3S,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]-3-chloro-4-fluorobenzamide (tonabelsat), or a hemichannel blocker of the following formula (I) or formula (II): 【Transformation 8】 In the formula, Y is C-R 1; R1 is acetyl; R2 is hydrogen, C3-8 cycloalkyl, optionally interrupted by oxygen, or substituted with hydroxy, C1-6 alkoxy or substituted aminocarbonyl C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyloxy, C1-6 alkoxy, nitro, cyano, halo, trifluoromethyl, or CF3S; or CF3-A-group, where A is -CF2-, -CO-, -CH2-, CH(OH), SO2, SO, CH2-O, or CONH; or CF2H-A'-group, where A' is oxygen, sulfur, SO, SO2, CF2, or CFH; trifluoromethoxy, C1-6 alkylsulfinyl, perfluoroC2-6 Alkylsulfonyl, C1-6 alkylsulfonyl, C1-6 alkoxysulfinyl, C1-6 alkoxysulfonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulfinyl, heteroarylsulfinyl, arylsulfonyl, or heteroarylsulfonyl (any aromatic part is optionally substituted), C1-6 alkylcarbonylamino, C1-6 alkoxycarbonylamino, C1-6 alkyl-thiocarbonyl, C1-6 alkoxy-thiocarbonyl, C1-6 alkyl-thiocarbonyloxy, 1-mercaptoC2-7 alkyl, formyl, or aminosulfinyl, aminosulfonyl or aminocarbonyl where any amino part is optionally substituted with one or two C1-6 alkyl groups, or C1-6 alkylsulfinylamino, C1-6 alkylsulfonylamino, C1-6 It is an alkoxysulfinylamino or C1-6 alkoxysulfonylamino, or an ethilenyl terminally substituted with a C1-6 alkylcarbonyl, nitro or cyano, or -C(C1-6 alkyl)NOH or -C(C1-6 alkyl)NNH2;or an amino that is optionally substituted with one or two C1-6 alkyl groups, or optionally substituted with a C2-7 alkanoyl group; One of R3 and R4 is hydrogen or a C1-4 alkyl group, and the other is a C1-4 alkyl group, CF3 or CH2Xa is a fluoro, chloro, bromo, iodo, C1-4 alkoxy, hydroxy, C1-4 alkylcarbonyloxy, -S-C1-4 alkyl, nitro, an amino, cyano, or C1-4 alkoxycarbonyl group optionally substituted with one or two C1-4 alkyl groups; or R3 and R4 are both C2-5 polymethylene groups optionally substituted with C1-4 alkyl groups; R5 is a C1-6 alkylcarbonyloxy, benzoyloxy, ONO2, benzyloxy, phenyloxy, or C1-6 alkoxy, and R6 and R9 are hydrogen, or R5 is hydroxyl, R6 is hydrogen or a C1-2 alkyl, and R9 is hydrogen; R7 is a heteroaryl or phenyl group, both of which are independently and optionally substituted once or twice with a group or atom selected from chloro, fluoro, bromo, iodo, nitro, or amino, in which case the amino group is optionally substituted once or twice with C1-4 alkyl, cyano, azide, C1-4 alkoxy, trifluoromethoxy, and trifluoromethyl groups; R8 is hydrogen, C1-6 alkyl, OR11 or NHCOR10, where R11 is hydrogen, C1-6 alkyl, formyl, C1-6 alkanoyl, aroyl or aryl-C1-6 alkyl; R10 is hydrogen, C1-6 alkyl, C1-6 alkoxy, mono or di-C1-6 alkylamino, amino-C1-6 alkyl, hydroxy-C1-6 alkyl, halo-C1-6 alkyl, C1-6 acyloxy-C1-6 alkyl, C1-6 alkoxycarbonyl-C1-6 alkyl, aryl or heteroaryl; the R8-N-CO-R7 group is cis relative to the R5 group; and X is oxygen or NR12, where R12 is hydrogen or C 1-6 alkyl; or formula II 【Chemistry 9】 During the ceremony, Q is O or the oxime of formula = NOR 43, where R 43 is (i) Selected from H, C1-4 fluoroalkyl, or optionally substituted C1-4 alkyl, (ii) -A 300 -R 300, where A 300 is directly bonded, -C(O)O*-, -C(R 3)(R 4)O*-, -C(O)O-C(R 3)(R 4)O*-, or -C(R 3)(R 4)OC(O)O*-, where the atom marked with * is directly bonded to R 300, R 3 and R 4 are independently selected from H, fluoro, C1-4 alkyl, or C1-4 fluoroalkyl, or R 3 and R 4 form a cyclopropyl group with the atom to which they are bonded, and R 300 is selected from the group [1], [2], [2A], [3], [4], [5] or [6]; R2 is H, A is directly bonded, -C(O)O*-, -C(R3)(R4)O*-, -C(O)O-C(R3)(R4)O*-, or -C(R3)(R4)OC(O)O*-, where the atom marked with * is directly bonded to R1, R3 and R4 are independently selected from H, fluoro, C1-4 alkyl, or C1-4 fluoroalkyl, or R3 and R4 together with the atom to which they are bonded form a cyclopropyl group. R1 is selected from the groups [1], [2], [2A], [3], [4], [5] and [6], and atoms marked with ** are directly attached to A. 【Chemistry 10】 R5 and R6 are independently selected from H, C1-4 alkyl, C1-4 fluoroalkyl, and benzyl; R7 is independently selected from H, C1-4 alkyl, and C1-4 fluoroalkyl; R 8 is, (i) H, C1-4 alkyl or C1-4 fluoroalkyl, or (ii) Side chains of natural or unnatural alpha-amino acids, (iii) Biotin, or a biotin-chemically linked substance Selected from; R9 is selected from H, -N(R11)(R12), or -N+(R11)(R12)(R13)X-, or -N(R11)C(O)R14. In the formula, R11, R12, and R13 are independently selected from H, C1-4 alkyl, or C1-4 fluoroalkyl. R14 is H, C1-4 alkyl, or C1-4 fluoroalkyl, R 15 is independently selected from C1-4 alkyl and C1-4 fluoroalkyl, and X- is a pharmaceutically acceptable anion. composition.

5. The composition according to any one of claims 1 to 3 or 4, wherein the hemichannel blocker is a connexin 43 hemichannel blocker.

6. The composition for use according to any one of claims 1 to 3 or 4, wherein the hemichannel blocker is N-[(3S,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]-3-chloro-4-fluorobenzamide (tonabelsat).

7. The hemichannel blocker is a hemichannel blocker of the following formula (I) or formula (II): 【Transformation 8】 In the formula, Y is C-R 1; R1 is acetyl; R2 is hydrogen, C3-8 cycloalkyl, optionally interrupted by oxygen, or substituted with hydroxy, C1-6 alkoxy or substituted aminocarbonyl C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyloxy, C1-6 alkoxy, nitro, cyano, halo, trifluoromethyl, or CF3S; or CF3-A-group, where A is -CF2-, -CO-, -CH2-, CH(OH), SO2, SO, CH2-O, or CONH; or CF2H-A'-group, where A' is oxygen, sulfur, SO, SO2, CF2, or CFH; trifluoromethoxy, C1-6 alkylsulfinyl, perfluoroC2-6 Alkylsulfonyl, C1-6 alkylsulfonyl, C1-6 alkoxysulfinyl, C1-6 alkoxysulfonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulfinyl, heteroarylsulfinyl, arylsulfonyl, or heteroarylsulfonyl (any aromatic part is optionally substituted), C1-6 alkylcarbonylamino, C1-6 alkoxycarbonylamino, C1-6 alkyl-thiocarbonyl, C1-6 alkoxy-thiocarbonyl, C1-6 alkyl-thiocarbonyloxy, 1-mercaptoC2-7 alkyl, formyl, or aminosulfinyl, aminosulfonyl or aminocarbonyl where any amino part is optionally substituted with one or two C1-6 alkyl groups, or C1-6 alkylsulfinylamino, C1-6 alkylsulfonylamino, C1-6 It is an alkoxysulfinylamino or C1-6 alkoxysulfonylamino, or an ethilenyl terminally substituted with a C1-6 alkylcarbonyl, nitro or cyano, or -C(C1-6 alkyl)NOH or -C(C1-6 alkyl)NNH2;or an amino that is optionally substituted with one or two C1-6 alkyl groups, or optionally substituted with a C2-7 alkanoyl group; One of R3 and R4 is hydrogen or a C1-4 alkyl group, and the other is a C1-4 alkyl group, CF3 or CH2Xa is a fluoro, chloro, bromo, iodo, C1-4 alkoxy, hydroxy, C1-4 alkylcarbonyloxy, -S-C1-4 alkyl, nitro, an amino, cyano, or C1-4 alkoxycarbonyl group optionally substituted with one or two C1-4 alkyl groups; or R3 and R4 are both C2-5 polymethylene groups optionally substituted with C1-4 alkyl groups; R5 is a C1-6 alkylcarbonyloxy, benzoyloxy, ONO2, benzyloxy, phenyloxy, or C1-6 alkoxy, and R6 and R9 are hydrogen, or R5 is hydroxyl, R6 is hydrogen or a C1-2 alkyl, and R9 is hydrogen; R7 is a heteroaryl or phenyl group, both of which are independently and optionally substituted once or twice with a group or atom selected from chloro, fluoro, bromo, iodo, nitro, or amino, in which case the amino group is optionally substituted once or twice with C1-4 alkyl, cyano, azide, C1-4 alkoxy, trifluoromethoxy, and trifluoromethyl groups; R8 is hydrogen, C1-6 alkyl, OR11 or NHCOR10, where R11 is hydrogen, C1-6 alkyl, formyl, C1-6 alkanoyl, aroyl or aryl-C1-6 alkyl; R10 is hydrogen, C1-6 alkyl, C1-6 alkoxy, mono or di-C1-6 alkylamino, amino-C1-6 alkyl, hydroxy-C1-6 alkyl, halo-C1-6 alkyl, C1-6 acyloxy-C1-6 alkyl, C1-6 alkoxycarbonyl-C1-6 alkyl, aryl or heteroaryl; the R8-N-CO-R7 group is cis relative to the R5 group; and X is oxygen or NR12, where R12 is hydrogen or C 1-6 alkyl; or formula II 【Chemistry 9】 During the ceremony, Q is O or the oxime of formula = NOR 43, where R 43 is (i) Selected from H, C1-4 fluoroalkyl, or optionally substituted C1-4 alkyl, (ii) -A 300 -R 300, where A 300 is a direct bond, -C(O)O*-, -C(R 3)(R 4)O*-, The formula is -C(O)O-C(R3)(R4)O*- or -C(R3)(R4)OC(O)O*-, where the atom marked with * is directly bonded to R300, R3 and R4 are independently selected from H, fluoro, C1-4 alkyl, or C1-4 fluoroalkyl, or R3 and R4 form a cyclopropyl group with the atom to which they are bonded, and R300 is selected from the group [1], [2], [2A], [3], [4], [5] or [6]; R2 is H, A is directly bonded, -C(O)O*-, -C(R3)(R4)O*-, -C(O)O-C(R3)(R4)O*-, or -C(R3)(R4)OC(O)O*-, where the atom marked with * is directly bonded to R1, R3 and R4 are independently selected from H, fluoro, C1-4 alkyl, or C1-4 fluoroalkyl, or R3 and R4 together with the atom to which they are bonded form a cyclopropyl group. R1 is selected from the groups [1], [2], [2A], [3], [4], [5] and [6], and atoms marked with ** are directly attached to A. 【Chemistry 10】 R5 and R6 are independently H, C1-4 alkyl, C1-4 fluoroalkyl, and Selected from benzyl; R7 is independently selected from H, C1-4 alkyl, and C1-4 fluoroalkyl; R 8 is, (i) H, C1-4 alkyl or C1-4 fluoroalkyl, or (ii) Side chains of natural or unnatural alpha-amino acids, (iii) Biotin, or a substance chemically linked to biotin, selected from; R9 is selected from H, -N(R11)(R12), or -N+(R11)(R12)(R13)X-, or -N(R11)C(O)R14. In the formula, R11, R12, and R13 are independently selected from H, C1-4 alkyl, or C1-4 fluoroalkyl. R14 is H, C1-4 alkyl, or C1-4 fluoroalkyl, R 15 is independently selected from C1-4 alkyl and C1-4 fluoroalkyl, and The composition according to any one of claims 1 to 3 or 4, wherein X- is a pharmaceutically acceptable anion.

8. The composition according to any one of claims 1 to 3 or 4, characterized in that the composition is administered orally in an amount ranging from 10 to 200 mg of the hemichannel blocker per day.

9. The composition according to claim 6, characterized in that the composition is administered orally in an amount ranging from 10 to 200 mg of the hemichannel blocker per day.

10. The composition according to claim 6, characterized in that the composition is administered orally in an amount of the hemichannel blocker in the range of 0.2 mg / kg to 5 mg / kg.

11. The composition according to claim 1, characterized in that the composition is administered by injection.

12. The composition according to claim 1, characterized in that the composition is administered orally.

13. The composition according to claim 1 to 3 or 4, characterized in that the composition is administered once a day.

14. The composition according to claim 1 to 3 or 4, characterized in that the composition is administered once a week.

15. The composition according to claim 6, wherein the subject is a human.

16. The composition according to claim 1, wherein the hemichannel blocker is not present in the composition containing microparticles.

17. The composition according to claim 1, wherein the retinal function is selected from mixed a-wave function, mixed b-wave function, and / or PII and PIII rod and cone functions.

18. A composition comprising a hemichannel blocker for use in a method of restoring or recovering the integrity of the retinal structure to a normal or pre-disease state in a subject having a chronic retinal disorder selected from the group consisting of diabetic retinopathy, nonproliferative diabetic retinopathy, diabetic macular edema, inflammatory or infectious choroiditis, and uveitis, wherein the improvement in the integrity of the retinal structure is measured by the recovery of the retinal vascular endothelium or the recovery of the normal retinal layer structure, and the hemichannel blocker is N-[(3S,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]-3-chloro-4-fluorobenzamide (tonabelsat), or a hemichannel blocker of the following formula (I) or formula (II): 【Transformation 8】 In the formula, Y is C-R 1; R1 is acetyl; R2 is hydrogen, C3-8 cycloalkyl, optionally interrupted by oxygen, or substituted with hydroxy, C1-6 alkoxy or substituted aminocarbonyl C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyloxy, C1-6 alkoxy, nitro, cyano, halo, trifluoromethyl, or CF3S; or CF3-A-group, where A is -CF2-, -CO-, -CH2-, CH(OH), SO2, SO, CH2-O, or CONH; or CF2H-A'-group, where A' is oxygen, sulfur, SO, SO2, CF2, or CFH; trifluoromethoxy, C1-6 alkylsulfinyl, perfluoroC2-6 Alkylsulfonyl, C1-6 alkylsulfonyl, C1-6 alkoxysulfinyl, C1-6 alkoxysulfonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulfinyl, heteroarylsulfinyl, arylsulfonyl, or heteroarylsulfonyl (any aromatic part is optionally substituted), C1-6 alkylcarbonylamino, C1-6 alkoxycarbonylamino, C1-6 alkyl-thiocarbonyl, C1-6 alkoxy-thiocarbonyl, C1-6 alkyl-thiocarbonyloxy, 1-mercaptoC2-7 alkyl, formyl, or aminosulfinyl, aminosulfonyl or aminocarbonyl where any amino part is optionally substituted with one or two C1-6 alkyl groups, or C1-6 alkylsulfinylamino, C1-6 alkylsulfonylamino, C1-6 It is an alkoxysulfinylamino or C1-6 alkoxysulfonylamino, or an ethilenyl terminally substituted with a C1-6 alkylcarbonyl, nitro or cyano, or -C(C1-6 alkyl)NOH or -C(C1-6 alkyl)NNH2;or an amino that is optionally substituted with one or two C1-6 alkyl groups, or optionally substituted with a C2-7 alkanoyl group; One of R3 and R4 is hydrogen or a C1-4 alkyl group, and the other is a C1-4 alkyl group, CF3 or CH2Xa is a fluoro, chloro, bromo, iodo, C1-4 alkoxy, hydroxy, C1-4 alkylcarbonyloxy, -S-C1-4 alkyl, nitro, an amino, cyano, or C1-4 alkoxycarbonyl group optionally substituted with one or two C1-4 alkyl groups; or R3 and R4 are both C2-5 polymethylene groups optionally substituted with C1-4 alkyl groups; R5 is a C1-6 alkylcarbonyloxy, benzoyloxy, ONO2, benzyloxy, phenyloxy, or C1-6 alkoxy, and R6 and R9 are hydrogen, or R5 is hydroxyl, R6 is hydrogen or a C1-2 alkyl, and R9 is hydrogen; R7 is a heteroaryl or phenyl group, both of which are independently and optionally substituted once or twice with a group or atom selected from chloro, fluoro, bromo, iodo, nitro, or amino, in which case the amino group is optionally substituted once or twice with C1-4 alkyl, cyano, azide, C1-4 alkoxy, trifluoromethoxy, and trifluoromethyl groups; R8 is hydrogen, C1-6 alkyl, OR11 or NHCOR10, where R11 is hydrogen, C1-6 alkyl, formyl, C1-6 alkanoyl, aroyl or aryl-C1-6 alkyl; R10 is hydrogen, C1-6 alkyl, C1-6 alkoxy, mono or di-C1-6 alkylamino, amino-C1-6 alkyl, hydroxy-C1-6 alkyl, halo-C1-6 alkyl, C1-6 acyloxy-C1-6 alkyl, C1-6 alkoxycarbonyl-C1-6 alkyl, aryl or heteroaryl; the R8-N-CO-R7 group is cis relative to the R5 group; and X is oxygen or NR12, where R12 is hydrogen or C 1-6 alkyl; or formula II 【Chemistry 9】 During the ceremony, Q is O or the oxime of formula = NOR 43, where R 43 is (i) Selected from H, C1-4 fluoroalkyl, or optionally substituted C1-4 alkyl, (ii) -A 300 -R 300, where A 300 is directly bonded, -C(O)O*-, -C(R 3)(R 4)O*-, -C(O)O-C(R 3)(R 4)O*-, or -C(R 3)(R 4)OC(O)O*-, where the atom marked with * is directly bonded to R 300, R 3 and R 4 are independently selected from H, fluoro, C1-4 alkyl, or C1-4 fluoroalkyl, or R 3 and R 4 form a cyclopropyl group with the atom to which they are bonded, and R 300 is selected from the group [1], [2], [2A], [3], [4], [5] or [6]; R2 is H, A is directly bonded, -C(O)O*-, -C(R3)(R4)O*-, -C(O)O-C(R3)(R4)O*-, or -C(R3)(R4)OC(O)O*-, where the atom marked with * is directly bonded to R1, R3 and R4 are independently selected from H, fluoro, C1-4 alkyl, or C1-4 fluoroalkyl, or R3 and R4 together with the atom to which they are bonded form a cyclopropyl group. R1 is selected from the groups [1], [2], [2A], [3], [4], [5] and [6], and atoms marked with ** are directly attached to A. 【Chemistry 10】 R5 and R6 are independently selected from H, C1-4 alkyl, C1-4 fluoroalkyl, and benzyl; R7 is independently selected from H, C1-4 alkyl, and C1-4 fluoroalkyl; R 8 is, (i) H, C1-4 alkyl or C1-4 fluoroalkyl, or (ii) Side chains of natural or unnatural alpha-amino acids, (iii) Biotin, or a biotin-chemically linked substance Selected from; R9 is selected from H, -N(R11)(R12), or -N+(R11)(R12)(R13)X-, or -N(R11)C(O)R14. In the formula, R11, R12, and R13 are independently selected from H, C1-4 alkyl, or C1-4 fluoroalkyl. R14 is H, C1-4 alkyl, or C1-4 fluoroalkyl, R 15 is independently selected from C1-4 alkyl and C1-4 fluoroalkyl, and X- is a pharmaceutically acceptable anion. composition.

19. A composition comprising a hemichannel blocker for use in a method of restoring or recovering microaneurysms and / or megaaneurysms to a normal or pre-disease state in subjects having a chronic retinal disorder selected from the group consisting of diabetic retinopathy, nonproliferative diabetic retinopathy, diabetic macular edema, inflammatory or infectious choroiditis, and uveitis, wherein the hemichannel blocker is N-[(3S,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]-3-chloro-4-fluorobenzamide (tonabelsat), or a hemichannel blocker of the following formula (I) or formula (II): 【Transformation 8】 In the formula, Y is C-R 1; R1 is acetyl; R2 is hydrogen, C3-8 cycloalkyl, optionally interrupted by oxygen, or substituted with hydroxy, C1-6 alkoxy or substituted aminocarbonyl C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyloxy, C1-6 alkoxy, nitro, cyano, halo, trifluoromethyl, or CF3S; or CF3-A-group, where A is -CF2-, -CO-, -CH2-, CH(OH), SO2, SO, CH2-O, or CONH; or CF2H-A'-group, where A' is oxygen, sulfur, SO, SO2, CF2, or CFH; trifluoromethoxy, C1-6 alkylsulfinyl, perfluoroC2-6 Alkylsulfonyl, C1-6 alkylsulfonyl, C1-6 alkoxysulfinyl, C1-6 alkoxysulfonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulfinyl, heteroarylsulfinyl, arylsulfonyl, or heteroarylsulfonyl (any aromatic part is optionally substituted), C1-6 alkylcarbonylamino, C1-6 alkoxycarbonylamino, C1-6 alkyl-thiocarbonyl, C1-6 alkoxy-thiocarbonyl, C1-6 alkyl-thiocarbonyloxy, 1-mercaptoC2-7 alkyl, formyl, or aminosulfinyl, aminosulfonyl or aminocarbonyl where any amino part is optionally substituted with one or two C1-6 alkyl groups, or C1-6 alkylsulfinylamino, C1-6 alkylsulfonylamino, C1-6 It is an alkoxysulfinylamino or C1-6 alkoxysulfonylamino, or an ethilenyl terminally substituted with a C1-6 alkylcarbonyl, nitro or cyano, or -C(C1-6 alkyl)NOH or -C(C1-6 alkyl)NNH2;or an amino that is optionally substituted with one or two C1-6 alkyl groups, or optionally substituted with a C2-7 alkanoyl group; One of R3 and R4 is hydrogen or a C1-4 alkyl group, and the other is a C1-4 alkyl group, CF3 or CH2Xa is a fluoro, chloro, bromo, iodo, C1-4 alkoxy, hydroxy, C1-4 alkylcarbonyloxy, -S-C1-4 alkyl, nitro, an amino, cyano, or C1-4 alkoxycarbonyl group optionally substituted with one or two C1-4 alkyl groups; or R3 and R4 are both C2-5 polymethylene groups optionally substituted with C1-4 alkyl groups; R5 is a C1-6 alkylcarbonyloxy, benzoyloxy, ONO2, benzyloxy, phenyloxy, or C1-6 alkoxy, and R6 and R9 are hydrogen, or R5 is hydroxyl, R6 is hydrogen or a C1-2 alkyl, and R9 is hydrogen; R7 is a heteroaryl or phenyl group, both of which are independently and optionally substituted once or twice with a group or atom selected from chloro, fluoro, bromo, iodo, nitro, or amino, in which case the amino group is optionally substituted once or twice with C1-4 alkyl, cyano, azide, C1-4 alkoxy, trifluoromethoxy, and trifluoromethyl groups; R8 is hydrogen, C1-6 alkyl, OR11 or NHCOR10, where R11 is hydrogen, C1-6 alkyl, formyl, C1-6 alkanoyl, aroyl or aryl-C1-6 alkyl; R10 is hydrogen, C1-6 alkyl, C1-6 alkoxy, mono or di-C1-6 alkylamino, amino-C1-6 alkyl, hydroxy-C1-6 alkyl, halo-C1-6 alkyl, C1-6 acyloxy-C1-6 alkyl, C1-6 alkoxycarbonyl-C1-6 alkyl, aryl or heteroaryl; the R8-N-CO-R7 group is cis relative to the R5 group; and X is oxygen or NR12, where R12 is hydrogen or C 1-6 alkyl; or formula II 【Chemistry 9】 During the ceremony, Q is O or the oxime of formula = NOR 43, where R 43 is (i) Selected from H, C1-4 fluoroalkyl, or optionally substituted C1-4 alkyl, (ii) -A 300 -R 300, where A 300 is directly bonded, -C(O)O*-, -C(R 3)(R 4)O*-, -C(O)O-C(R 3)(R 4)O*-, or -C(R 3)(R 4)OC(O)O*-, where the atom marked with * is directly bonded to R 300, R 3 and R 4 are independently selected from H, fluoro, C1-4 alkyl, or C1-4 fluoroalkyl, or R 3 and R 4 form a cyclopropyl group with the atom to which they are bonded, and R 300 is selected from the group [1], [2], [2A], [3], [4], [5] or [6]; R2 is H, A is directly bonded, -C(O)O*-, -C(R3)(R4)O*-, -C(O)O-C(R3)(R4)O*-, or -C(R3)(R4)OC(O)O*-, where the atom marked with * is directly bonded to R1, R3 and R4 are independently selected from H, fluoro, C1-4 alkyl, or C1-4 fluoroalkyl, or R3 and R4 together with the atom to which they are bonded form a cyclopropyl group. R1 is selected from the groups [1], [2], [2A], [3], [4], [5] and [6], and atoms marked with ** are directly attached to A. 【Chemistry 10】 R5 and R6 are independently selected from H, C1-4 alkyl, C1-4 fluoroalkyl, and benzyl; R7 is independently selected from H, C1-4 alkyl, and C1-4 fluoroalkyl; R 8 is, (i) H, C1-4 alkyl or C1-4 fluoroalkyl, or (ii) Side chains of natural or unnatural alpha-amino acids, (iii) Biotin, or a biotin-chemically linked substance Selected from; R9 is selected from H, -N(R11)(R12), or -N+(R11)(R12)(R13)X-, or -N(R11)C(O)R14. In the formula, R11, R12, and R13 are independently selected from H, C1-4 alkyl, or C1-4 fluoroalkyl. R14 is H, C1-4 alkyl, or C1-4 fluoroalkyl, R 15 is independently selected from C1-4 alkyl and C1-4 fluoroalkyl, and X- is a pharmaceutically acceptable anion. composition.

20. A composition comprising a hemichannel blocker for use in a method of restoring or recovering the function of photoreceptors to a normal or pre-disease state in a subject having a chronic retinal disorder selected from the group consisting of diabetic retinopathy, nonproliferative diabetic retinopathy, diabetic macular edema, inflammatory or infectious choroiditis, and uveitis, wherein the hemichannel blocker is N-[(3S,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]-3-chloro-4-fluorobenzamide (tonabelsat), or a hemichannel blocker of the following formula (I) or formula (II): 【Transformation 8】 In the formula, Y is C-R 1; R1 is acetyl; R2 is hydrogen, C3-8 cycloalkyl, optionally interrupted by oxygen, or substituted with hydroxy, C1-6 alkoxy or substituted aminocarbonyl C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyloxy, C1-6 alkoxy, nitro, cyano, halo, trifluoromethyl, or CF3S; or CF3-A-group, where A is -CF2-, -CO-, -CH2-, CH(OH), SO2, SO, CH2-O, or CONH; or CF2H-A'-group, where A' is oxygen, sulfur, SO, SO2, CF2, or CFH; trifluoromethoxy, C1-6 alkylsulfinyl, perfluoroC2-6 Alkylsulfonyl, C1-6 alkylsulfonyl, C1-6 alkoxysulfinyl, C1-6 alkoxysulfonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulfinyl, heteroarylsulfinyl, arylsulfonyl, or heteroarylsulfonyl (any aromatic part is optionally substituted), C1-6 alkylcarbonylamino, C1-6 alkoxycarbonylamino, C1-6 alkyl-thiocarbonyl, C1-6 alkoxy-thiocarbonyl, C1-6 alkyl-thiocarbonyloxy, 1-mercaptoC2-7 alkyl, formyl, or aminosulfinyl, aminosulfonyl or aminocarbonyl where any amino part is optionally substituted with one or two C1-6 alkyl groups, or C1-6 alkylsulfinylamino, C1-6 alkylsulfonylamino, C1-6 It is an alkoxysulfinylamino or C1-6 alkoxysulfonylamino, or an ethilenyl terminally substituted with a C1-6 alkylcarbonyl, nitro or cyano, or -C(C1-6 alkyl)NOH or -C(C1-6 alkyl)NNH2;or an amino that is optionally substituted with one or two C1-6 alkyl groups, or optionally substituted with a C2-7 alkanoyl group; One of R3 and R4 is hydrogen or a C1-4 alkyl group, and the other is a C1-4 alkyl group, CF3 or CH2Xa is a fluoro, chloro, bromo, iodo, C1-4 alkoxy, hydroxy, C1-4 alkylcarbonyloxy, -S-C1-4 alkyl, nitro, an amino, cyano, or C1-4 alkoxycarbonyl group optionally substituted with one or two C1-4 alkyl groups; or R3 and R4 are both C2-5 polymethylene groups optionally substituted with C1-4 alkyl groups; R5 is a C1-6 alkylcarbonyloxy, benzoyloxy, ONO2, benzyloxy, phenyloxy, or C1-6 alkoxy, and R6 and R9 are hydrogen, or R5 is hydroxyl, R6 is hydrogen or a C1-2 alkyl, and R9 is hydrogen; R7 is a heteroaryl or phenyl group, both of which are independently and optionally substituted once or twice with a group or atom selected from chloro, fluoro, bromo, iodo, nitro, or amino, in which case the amino group is optionally substituted once or twice with C1-4 alkyl, cyano, azide, C1-4 alkoxy, trifluoromethoxy, and trifluoromethyl groups; R8 is hydrogen, C1-6 alkyl, OR11 or NHCOR10, where R11 is hydrogen, C1-6 alkyl, formyl, C1-6 alkanoyl, aroyl or aryl-C1-6 alkyl; R10 is hydrogen, C1-6 alkyl, C1-6 alkoxy, mono or di-C1-6 alkylamino, amino-C1-6 alkyl, hydroxy-C1-6 alkyl, halo-C1-6 alkyl, C1-6 acyloxy-C1-6 alkyl, C1-6 alkoxycarbonyl-C1-6 alkyl, aryl or heteroaryl; the R8-N-CO-R7 group is cis relative to the R5 group; and X is oxygen or NR12, where R12 is hydrogen or C 1-6 alkyl; or formula II 【Chemistry 9】 During the ceremony, Q is O or the oxime of formula = NOR 43, where R 43 is (i) Selected from H, C1-4 fluoroalkyl, or optionally substituted C1-4 alkyl, (ii) -A 300 -R 300, where A 300 is directly bonded, -C(O)O*-, -C(R 3)(R 4)O*-, -C(O)O-C(R 3)(R 4)O*-, or -C(R 3)(R 4)OC(O)O*-, where the atom marked with * is directly bonded to R 300, R 3 and R 4 are independently selected from H, fluoro, C1-4 alkyl, or C1-4 fluoroalkyl, or R 3 and R 4 form a cyclopropyl group with the atom to which they are bonded, and R 300 is selected from the group [1], [2], [2A], [3], [4], [5] or [6]; R2 is H, A is directly bonded, -C(O)O*-, -C(R3)(R4)O*-, -C(O)O-C(R3)(R4)O*-, or -C(R3)(R4)OC(O)O*-, where the atom marked with * is directly bonded to R1, R3 and R4 are independently selected from H, fluoro, C1-4 alkyl, or C1-4 fluoroalkyl, or R3 and R4 together with the atom to which they are bonded form a cyclopropyl group. R1 is selected from the groups [1], [2], [2A], [3], [4], [5] and [6], and atoms marked with ** are directly attached to A. 【Chemistry 10】 R5 and R6 are independently selected from H, C1-4 alkyl, C1-4 fluoroalkyl, and benzyl; R7 is independently selected from H, C1-4 alkyl, and C1-4 fluoroalkyl; R 8 is, (i) H, C1-4 alkyl or C1-4 fluoroalkyl, or (ii) Side chains of natural or unnatural alpha-amino acids, (iii) Biotin, or a biotin-chemically linked substance Selected from; R9 is selected from H, -N(R11)(R12), or -N+(R11)(R12)(R13)X-, or -N(R11)C(O)R14. In the formula, R11, R12, and R13 are independently selected from H, C1-4 alkyl, or C1-4 fluoroalkyl. R14 is H, C1-4 alkyl, or C1-4 fluoroalkyl, R 15 is independently selected from C1-4 alkyl and C1-4 fluoroalkyl, and X- is a pharmaceutically acceptable anion. composition.

21. A composition comprising a hemichannel blocker for use in a method for improving the integrity of choroidal structure in a subject having a chronic retinal disorder selected from the group consisting of diabetic retinopathy, nonproliferative diabetic retinopathy, diabetic macular edema, inflammatory or infectious choroiditis, and uveitis, wherein the integrity of retinal structure is measured by the restoration of choroidal thickness or the restoration of the choroidal vascular bed, wherein the hemichannel blocker is N-[(3S,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]-3-chloro-4-fluorobenzamide (tonaversat), or a hemichannel blocker of the following formula (I) or formula (II): 【Transformation 8】 In the formula, Y is C-R 1; R1 is acetyl; R2 is hydrogen, C3-8 cycloalkyl, optionally interrupted by oxygen, or substituted with hydroxy, C1-6 alkoxy or substituted aminocarbonyl C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyloxy, C1-6 alkoxy, nitro, cyano, halo, trifluoromethyl, or CF3S; or CF3-A-group, where A is -CF2-, -CO-, -CH2-, CH(OH), SO2, SO, CH2-O, or CONH; or CF2H-A'-group, where A' is oxygen, sulfur, SO, SO2, CF2, or CFH; trifluoromethoxy, C1-6 alkylsulfinyl, perfluoroC2-6 Alkylsulfonyl, C1-6 alkylsulfonyl, C1-6 alkoxysulfinyl, C1-6 alkoxysulfonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulfinyl, heteroarylsulfinyl, arylsulfonyl, or heteroarylsulfonyl (any aromatic part is optionally substituted), C1-6 alkylcarbonylamino, C1-6 alkoxycarbonylamino, C1-6 alkyl-thiocarbonyl, C1-6 alkoxy-thiocarbonyl, C1-6 alkyl-thiocarbonyloxy, 1-mercaptoC2-7 alkyl, formyl, or aminosulfinyl, aminosulfonyl or aminocarbonyl where any amino part is optionally substituted with one or two C1-6 alkyl groups, or C1-6 alkylsulfinylamino, C1-6 alkylsulfonylamino, C1-6 It is an alkoxysulfinylamino or C1-6 alkoxysulfonylamino, or an ethilenyl terminally substituted with a C1-6 alkylcarbonyl, nitro or cyano, or -C(C1-6 alkyl)NOH or -C(C1-6 alkyl)NNH2;or an amino that is optionally substituted with one or two C1-6 alkyl groups, or optionally substituted with a C2-7 alkanoyl group; One of R3 and R4 is hydrogen or a C1-4 alkyl group, and the other is a C1-4 alkyl group, CF3 or CH2Xa is a fluoro, chloro, bromo, iodo, C1-4 alkoxy, hydroxy, C1-4 alkylcarbonyloxy, -S-C1-4 alkyl, nitro, an amino, cyano, or C1-4 alkoxycarbonyl group optionally substituted with one or two C1-4 alkyl groups; or R3 and R4 are both C2-5 polymethylene groups optionally substituted with C1-4 alkyl groups; R5 is a C1-6 alkylcarbonyloxy, benzoyloxy, ONO2, benzyloxy, phenyloxy, or C1-6 alkoxy, and R6 and R9 are hydrogen, or R5 is hydroxyl, R6 is hydrogen or a C1-2 alkyl, and R9 is hydrogen; R7 is a heteroaryl or phenyl group, both of which are independently and optionally substituted once or twice with a group or atom selected from chloro, fluoro, bromo, iodo, nitro, or amino, in which case the amino group is optionally substituted once or twice with C1-4 alkyl, cyano, azide, C1-4 alkoxy, trifluoromethoxy, and trifluoromethyl groups; R8 is hydrogen, C1-6 alkyl, OR11 or NHCOR10, where R11 is hydrogen, C1-6 alkyl, formyl, C1-6 alkanoyl, aroyl or aryl-C1-6 alkyl; R10 is hydrogen, C1-6 alkyl, C1-6 alkoxy, mono or di-C1-6 alkylamino, amino-C1-6 alkyl, hydroxy-C1-6 alkyl, halo-C1-6 alkyl, C1-6 acyloxy-C1-6 alkyl, C1-6 alkoxycarbonyl-C1-6 alkyl, aryl or heteroaryl; the R8-N-CO-R7 group is cis relative to the R5 group; and X is oxygen or NR12, where R12 is hydrogen or C 1-6 alkyl; or formula II 【Chemistry 9】 During the ceremony, Q is O or the oxime of formula = NOR 43, where R 43 is (i) Selected from H, C1-4 fluoroalkyl, or optionally substituted C1-4 alkyl, (ii) -A 300 -R 300, where A 300 is directly bonded, -C(O)O*-, -C(R 3)(R 4)O*-, -C(O)O-C(R 3)(R 4)O*-, or -C(R 3)(R 4)OC(O)O*-, where the atom marked with * is directly bonded to R 300, R 3 and R 4 are independently selected from H, fluoro, C1-4 alkyl, or C1-4 fluoroalkyl, or R 3 and R 4 form a cyclopropyl group with the atom to which they are bonded, and R 300 is selected from the group [1], [2], [2A], [3], [4], [5] or [6]; R2 is H, A is directly bonded, -C(O)O*-, -C(R3)(R4)O*-, -C(O)O-C(R3)(R4)O*-, or -C(R3)(R4)OC(O)O*-, where the atom marked with * is directly bonded to R1, R3 and R4 are independently selected from H, fluoro, C1-4 alkyl, or C1-4 fluoroalkyl, or R3 and R4 together with the atom to which they are bonded form a cyclopropyl group. R1 is selected from the groups [1], [2], [2A], [3], [4], [5] and [6], and atoms marked with ** are directly attached to A. 【Chemistry 10】 R5 and R6 are independently selected from H, C1-4 alkyl, C1-4 fluoroalkyl, and benzyl; R7 is independently selected from H, C1-4 alkyl, and C1-4 fluoroalkyl; R 8 is, (i) H, C1-4 alkyl or C1-4 fluoroalkyl, or (ii) Side chains of natural or unnatural alpha-amino acids, (iii) Biotin, or a biotin-chemically linked substance Selected from; R9 is selected from H, -N(R11)(R12), or -N+(R11)(R12)(R13)X-, or -N(R11)C(O)R14. In the formula, R11, R12, and R13 are independently selected from H, C1-4 alkyl, or C1-4 fluoroalkyl. R14 is H, C1-4 alkyl, or C1-4 fluoroalkyl, R 15 is independently selected from C1-4 alkyl and C1-4 fluoroalkyl, and X- is a pharmaceutically acceptable anion. composition.

22. A composition comprising a hemichannel blocker for use in a method for improving blood flow to the outer retina of choroidal vessels in a subject having a chronic retinal disorder selected from the group consisting of diabetic retinopathy, nonproliferative diabetic retinopathy, diabetic macular edema, inflammatory or infectious choroiditis, and uveitis, wherein the hemichannel blocker is N-[(3S,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]-3-chloro-4-fluorobenzamide (tonabelsat), or a hemichannel blocker of the following formula (I) or formula (II): 【Transformation 8】 In the formula, Y is C-R 1; R1 is acetyl; R2 is hydrogen, C3-8 cycloalkyl, optionally interrupted by oxygen, or substituted with hydroxy, C1-6 alkoxy or substituted aminocarbonyl C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyloxy, C1-6 alkoxy, nitro, cyano, halo, trifluoromethyl, or CF3S; or CF3-A-group, where A is -CF2-, -CO-, -CH2-, CH(OH), SO2, SO, CH2-O, or CONH; or CF2H-A'-group, where A' is oxygen, sulfur, SO, SO2, CF2, or CFH; trifluoromethoxy, C1-6 alkylsulfinyl, perfluoroC2-6 Alkylsulfonyl, C1-6 alkylsulfonyl, C1-6 alkoxysulfinyl, C1-6 alkoxysulfonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulfinyl, heteroarylsulfinyl, arylsulfonyl, or heteroarylsulfonyl (any aromatic part is optionally substituted), C1-6 alkylcarbonylamino, C1-6 alkoxycarbonylamino, C1-6 alkyl-thiocarbonyl, C1-6 alkoxy-thiocarbonyl, C1-6 alkyl-thiocarbonyloxy, 1-mercaptoC2-7 alkyl, formyl, or aminosulfinyl, aminosulfonyl or aminocarbonyl where any amino part is optionally substituted with one or two C1-6 alkyl groups, or C1-6 alkylsulfinylamino, C1-6 alkylsulfonylamino, C1-6 It is an alkoxysulfinylamino or C1-6 alkoxysulfonylamino, or an ethilenyl terminally substituted with a C1-6 alkylcarbonyl, nitro or cyano, or -C(C1-6 alkyl)NOH or -C(C1-6 alkyl)NNH2;or an amino that is optionally substituted with one or two C1-6 alkyl groups, or optionally substituted with a C2-7 alkanoyl group; One of R3 and R4 is hydrogen or a C1-4 alkyl group, and the other is a C1-4 alkyl group, CF3 or CH2Xa is a fluoro, chloro, bromo, iodo, C1-4 alkoxy, hydroxy, C1-4 alkylcarbonyloxy, -S-C1-4 alkyl, nitro, an amino, cyano, or C1-4 alkoxycarbonyl group optionally substituted with one or two C1-4 alkyl groups; or R3 and R4 are both C2-5 polymethylene groups optionally substituted with C1-4 alkyl groups; R5 is a C1-6 alkylcarbonyloxy, benzoyloxy, ONO2, benzyloxy, phenyloxy, or C1-6 alkoxy, and R6 and R9 are hydrogen, or R5 is hydroxyl, R6 is hydrogen or a C1-2 alkyl, and R9 is hydrogen; R7 is a heteroaryl or phenyl group, both of which are independently and optionally substituted once or twice with a group or atom selected from chloro, fluoro, bromo, iodo, nitro, or amino, in which case the amino group is optionally substituted once or twice with C1-4 alkyl, cyano, azide, C1-4 alkoxy, trifluoromethoxy, and trifluoromethyl groups; R8 is hydrogen, C1-6 alkyl, OR11 or NHCOR10, where R11 is hydrogen, C1-6 alkyl, formyl, C1-6 alkanoyl, aroyl or aryl-C1-6 alkyl; R10 is hydrogen, C1-6 alkyl, C1-6 alkoxy, mono or di-C1-6 alkylamino, amino-C1-6 alkyl, hydroxy-C1-6 alkyl, halo-C1-6 alkyl, C1-6 acyloxy-C1-6 alkyl, C1-6 alkoxycarbonyl-C1-6 alkyl, aryl or heteroaryl; the R8-N-CO-R7 group is cis relative to the R5 group; and X is oxygen or NR12, where R12 is hydrogen or C 1-6 alkyl; or formula II 【Chemistry 9】 During the ceremony, Q is O or the oxime of formula = NOR 43, where R 43 is (i) Selected from H, C1-4 fluoroalkyl, or optionally substituted C1-4 alkyl, (ii) -A 300 -R 300, where A 300 is directly bonded, -C(O)O*-, -C(R 3)(R 4)O*-, -C(O)O-C(R 3)(R 4)O*-, or -C(R 3)(R 4)OC(O)O*-, where the atom marked with * is directly bonded to R 300, R 3 and R 4 are independently selected from H, fluoro, C1-4 alkyl, or C1-4 fluoroalkyl, or R 3 and R 4 form a cyclopropyl group with the atom to which they are bonded, and R 300 is selected from the group [1], [2], [2A], [3], [4], [5] or [6]; R2 is H, A is directly bonded, -C(O)O*-, -C(R3)(R4)O*-, -C(O)O-C(R3)(R4)O*-, or -C(R3)(R4)OC(O)O*-, where the atom marked with * is directly bonded to R1, R3 and R4 are independently selected from H, fluoro, C1-4 alkyl, or C1-4 fluoroalkyl, or R3 and R4 together with the atom to which they are bonded form a cyclopropyl group. R1 is selected from the groups [1], [2], [2A], [3], [4], [5] and [6], and atoms marked with ** are directly attached to A. 【Chemistry 10】 R5 and R6 are independently selected from H, C1-4 alkyl, C1-4 fluoroalkyl, and benzyl; R7 is independently selected from H, C1-4 alkyl, and C1-4 fluoroalkyl; R 8 is, (i) H, C1-4 alkyl or C1-4 fluoroalkyl, or (ii) Side chains of natural or unnatural alpha-amino acids, (iii) Biotin, or a biotin-chemically linked substance Selected from; R9 is selected from H, -N(R11)(R12), or -N+(R11)(R12)(R13)X-, or -N(R11)C(O)R14. In the formula, R11, R12, and R13 are independently selected from H, C1-4 alkyl, or C1-4 fluoroalkyl. R14 is H, C1-4 alkyl, or C1-4 fluoroalkyl, R 15 is independently selected from C1-4 alkyl and C1-4 fluoroalkyl, and X- is a pharmaceutically acceptable anion. composition.

23. A composition comprising a hemichannel blocker for use in a method for improving choroidal blood flow in a subject having a chronic retinal disorder selected from the group consisting of diabetic retinopathy, nonproliferative diabetic retinopathy, diabetic macular edema, inflammatory or infectious choroiditis, and uveitis, wherein the hemichannel blocker is N-[(3S,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]-3-chloro-4-fluorobenzamide (tonabelsat), or a hemichannel blocker of the following formula (I) or formula (II): 【Transformation 8】 In the formula, Y is C-R 1; R1 is acetyl; R2 is hydrogen, C3-8 cycloalkyl, optionally interrupted by oxygen, or substituted with hydroxy, C1-6 alkoxy or substituted aminocarbonyl C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyloxy, C1-6 alkoxy, nitro, cyano, halo, trifluoromethyl, or CF3S; or CF3-A-group, where A is -CF2-, -CO-, -CH2-, CH(OH), SO2, SO, CH2-O, or CONH; or CF2H-A'-group, where A' is oxygen, sulfur, SO, SO2, CF2, or CFH; trifluoromethoxy, C1-6 alkylsulfinyl, perfluoroC2-6 Alkylsulfonyl, C1-6 alkylsulfonyl, C1-6 alkoxysulfinyl, C1-6 alkoxysulfonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulfinyl, heteroarylsulfinyl, arylsulfonyl, or heteroarylsulfonyl (any aromatic part is optionally substituted), C1-6 alkylcarbonylamino, C1-6 alkoxycarbonylamino, C1-6 alkyl-thiocarbonyl, C1-6 alkoxy-thiocarbonyl, C1-6 alkyl-thiocarbonyloxy, 1-mercaptoC2-7 alkyl, formyl, or aminosulfinyl, aminosulfonyl or aminocarbonyl where any amino part is optionally substituted with one or two C1-6 alkyl groups, or C1-6 alkylsulfinylamino, C1-6 alkylsulfonylamino, C1-6 It is an alkoxysulfinylamino or C1-6 alkoxysulfonylamino, or an ethilenyl terminally substituted with a C1-6 alkylcarbonyl, nitro or cyano, or -C(C1-6 alkyl)NOH or -C(C1-6 alkyl)NNH2;or an amino that is optionally substituted with one or two C1-6 alkyl groups, or optionally substituted with a C2-7 alkanoyl group; One of R3 and R4 is hydrogen or a C1-4 alkyl group, and the other is a C1-4 alkyl group, CF3 or CH2Xa is a fluoro, chloro, bromo, iodo, C1-4 alkoxy, hydroxy, C1-4 alkylcarbonyloxy, -S-C1-4 alkyl, nitro, an amino, cyano, or C1-4 alkoxycarbonyl group optionally substituted with one or two C1-4 alkyl groups; or R3 and R4 are both C2-5 polymethylene groups optionally substituted with C1-4 alkyl groups; R5 is a C1-6 alkylcarbonyloxy, benzoyloxy, ONO2, benzyloxy, phenyloxy, or C1-6 alkoxy, and R6 and R9 are hydrogen, or R5 is hydroxyl, R6 is hydrogen or a C1-2 alkyl, and R9 is hydrogen; R7 is a heteroaryl or phenyl group, both of which are independently and optionally substituted once or twice with a group or atom selected from chloro, fluoro, bromo, iodo, nitro, or amino, in which case the amino group is optionally substituted once or twice with C1-4 alkyl, cyano, azide, C1-4 alkoxy, trifluoromethoxy, and trifluoromethyl groups; R8 is hydrogen, C1-6 alkyl, OR11 or NHCOR10, where R11 is hydrogen, C1-6 alkyl, formyl, C1-6 alkanoyl, aroyl or aryl-C1-6 alkyl; R10 is hydrogen, C1-6 alkyl, C1-6 alkoxy, mono or di-C1-6 alkylamino, amino-C1-6 alkyl, hydroxy-C1-6 alkyl, halo-C1-6 alkyl, C1-6 acyloxy-C1-6 alkyl, C1-6 alkoxycarbonyl-C1-6 alkyl, aryl or heteroaryl; the R8-N-CO-R7 group is cis relative to the R5 group; and X is oxygen or NR12, where R12 is hydrogen or C 1-6 alkyl; or formula II 【Chemistry 9】 During the ceremony, Q is O or the oxime of formula = NOR 43, where R 43 is (i) Selected from H, C1-4 fluoroalkyl, or optionally substituted C1-4 alkyl, (ii) -A 300 -R 300, where A 300 is directly bonded, -C(O)O*-, -C(R 3)(R 4)O*-, -C(O)O-C(R 3)(R 4)O*-, or -C(R 3)(R 4)OC(O)O*-, where the atom marked with * is directly bonded to R 300, R 3 and R 4 are independently selected from H, fluoro, C1-4 alkyl, or C1-4 fluoroalkyl, or R 3 and R 4 form a cyclopropyl group with the atom to which they are bonded, and R 300 is selected from the group [1], [2], [2A], [3], [4], [5] or [6]; R2 is H, A is directly bonded, -C(O)O*-, -C(R3)(R4)O*-, -C(O)O-C(R3)(R4)O*-, or -C(R3)(R4)OC(O)O*-, where the atom marked with * is directly bonded to R1, R3 and R4 are independently selected from H, fluoro, C1-4 alkyl, or C1-4 fluoroalkyl, or R3 and R4 together with the atom to which they are bonded form a cyclopropyl group. R1 is selected from the groups [1], [2], [2A], [3], [4], [5] and [6], and atoms marked with ** are directly attached to A. 【Chemistry 10】 R5 and R6 are independently selected from H, C1-4 alkyl, C1-4 fluoroalkyl, and benzyl; R7 is independently selected from H, C1-4 alkyl, and C1-4 fluoroalkyl; R 8 is, (i) H, C1-4 alkyl or C1-4 fluoroalkyl, or (ii) Side chains of natural or unnatural alpha-amino acids, (iii) Biotin, or a biotin-chemically linked substance Selected from; R9 is selected from H, -N(R11)(R12), or -N+(R11)(R12)(R13)X-, or -N(R11)C(O)R14. In the formula, R11, R12, and R13 are independently selected from H, C1-4 alkyl, or C1-4 fluoroalkyl. R14 is H, C1-4 alkyl, or C1-4 fluoroalkyl, R 15 is independently selected from C1-4 alkyl and C1-4 fluoroalkyl, and X- is a pharmaceutically acceptable anion. composition.

24. A composition comprising N-[(3S,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromemen-4-yl]-3-chloro-4-fluorobenzamide (Xiflam) for use in a method for increasing residual choroidal function in subjects having diabetic retinopathy, nonproliferative diabetic retinopathy, or diabetic macular edema, characterized in that the composition is administered to the subject in an amount of 10 to 200 mg of N-[(3S,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromemen-4-yl]-3-chloro-4-fluorobenzamide (Xiflam) per day.

25. The composition for use according to claim 24, wherein increasing the remaining choroidal function results in improved blood flow to the choroid.

26. The composition for use according to claim 24, wherein increasing the remaining choroidal function results in improved blood flow in choroidal blood vessels supplying the extrinsic retina.

27. ​​The composition for use according to claim 24, wherein increasing the remaining choroidal function results in improved regulation of choroidal blood flow.

28. A composition comprising N-[(3S,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromemen-4-yl]-3-chloro-4-fluorobenzamide (Xiflam) for use in a method for increasing the retention of choroidal structure in a subject having diabetic retinopathy, nonproliferative diabetic retinopathy, or diabetic macular edema, characterized in that the composition is administered to the subject in an amount of 10 to 200 mg of N-[(3S,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromemen-4-yl]-3-chloro-4-fluorobenzamide (Xiflam) per day.

29. The composition according to claim 28, wherein increasing the retention of choroidal structure results in an improvement in choroidal thickness.

30. The composition for use according to claim 28, wherein increasing the retention of choroidal structure results in an improvement in the choroidal vascular bed.

31. The composition according to claim 24, wherein increasing the remaining choroidal function results in the recovery or restoration of choroidal function.

32. The composition according to claim 28, wherein increasing the remaining choroidal structure restores or reconstructs the choroidal structure.

33. The composition according to any one of claims 1 to 3 or 4, wherein restoration or recovery is achieved by returning to a normal state or a pre-disease state.

34. The composition according to any one of claims 21, 22, or 23, wherein the improvement is achieved by restoring the body to a normal state or a pre-disease state.

35. The composition according to any one of claims 25 to 27, 29, or 30, wherein the improvement is achieved by returning to a normal state or a pre-disease state.

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