Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/06—Antiglaucoma agents or miotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates in general to therapeutic compositions and methods of use.
• the invention relates to the field of eye health.
• the ' invention relates to the prevention and treatment of macular degeneration by administering compounds disclosed herein.
• the invention relates to compositions and methods of improving vision.
• Aging is a chronic process causing degeneration of cells, tissues, and organs, including choroidal blood vessels, retinal pigment epithelium cells (RPEC) and Bruch's membrane of the eye.
• Arteriosclerotic aging changes choroids blood vessels, particularly the macular chorio-capillaris with a decrease in total capillary membrane blood flow.
• retinal pigment epithelium starts to accumulate lipofuscin, alters cell shape, density, pigmentation, lysosomal activity and extracellular matrix formation.
• Bruch's membrane shows thickening and decreased permeability, resulting with breakdown that allows choroidal neovascularization (CNV) to appear ultimately resulting in age-related macular degeneration and blindness.
• CNV choroidal neovascularization
• the present invention relates in general to therapeutic compositions and methods of use.
• the invention relates to the field of eye health.
• the invention relates to the prevention and treatment of macular degeneration by administering compounds disclosed herein.
• the invention relates to compositions and methods of improving vision.
• Ischemia of choroidal blood flow is one of the major causes of age-related macular degeneration (AMD). Therefore, agents have been discovered to prevent AMD formation via increasing of choroidal blood flow as measured with colored micro-sphere technique, retinal function recovery after ischemic insult, and inhibition of choroidal neovascularization in a laser treated rat model.
• agents include: hypotensive agents, such as hydralazine, guanabenz, and D-timolol; flavonoids, such as apigenin, naringenin, quercetin, and flavon; and N-nitropyrazoles and C-nitro-pyrazoles, such as DN6, DN7, DNl 3, and DC-5.
• CNV choroidal neovascularization
• agents as demonstrated herein, prevent AMD by preventing or reducing CNV.
• the invention relates to methods of identifying a compound capable of treating an eye disease, preferably macular degeneration, using method disclosed herein.
• Preferred methods include providing ischemic insult, measuring retinal function recovery, and correlating inhibition of neovascularization to a compound effective for preventing or treating eye diseases.
• the effective amount of the agent is between 0.1 and 250 mg/kg of the patient's weight, depending on the amount of active agent required and as taught herein.
• the agent may be adapted for oral, parenteral, intravenous, topical, intracameral or intraocular administration.
• the agent is provided in dry form, e.g., lyophilized and may be resuspended using, e.g., saline, buffered saline and the like.
• the agent may be combined with a suitable carrier, e.g., an anionic, mucomimetic polymer; a gelling polysaccharide; a finely-divided drug carrier substrate; a mineral oil; a liquid petrolatum; a white petrolatum; a propylene glycol; a polyoxyethylene; a polyoxypropylene; an emulsifying wax; water and mixtures and combinations thereof.
• a suitable carrier e.g., an anionic, mucomimetic polymer; a gelling polysaccharide; a finely-divided drug carrier substrate; a mineral oil; a liquid petrolatum; a white petrolatum; a propylene glycol; a polyoxyethylene; a polyoxypropylene; an emulsifying wax; water and mixtures and combinations thereof.
• the present invention also includes a method for treating, preventing or managing age-related macular degeneration by administering to a subject in need thereof a composition that includes an effective amount of an agent that increases choroidal blood flow.
• the composition may be administered after the occurrence of an acute ischemic trauma event, may be used before any symptoms are visible or detectable, during and/or after ischemic trauma.
• the subject may be any mammal, e.g., the subject may be a human.
• the effective amount of the agent for pre-treatment, treatment or even post operative treatment may be determined by measuring one or more retinal and/or choroidal functions during the recovery after an ischemic insult. Depending on the one or more agents selected for treatment, these may be provided to maximize the effectiveness of the agent, e.g., the effective amount of the agent may be between about 0.1 to about 250 mg/Kg depending on the patient's current and future needs for treatment.
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject diagnosed with or at risk for macular degeneration and ii) a composition comprising compounds disclosed herein or salt thereof and substituted and unsubstituted derivatives thereof functioning to decrease choroidal neovascularization and 2) administering said compound to said subject.
• said eye disease is age-related macular degeneration.
• said subject is a human.
• said administration is topically to the eye.
• said salt is a hydrochloride salt.
• said composition is a liquid solution.
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject that exhibits a symptom of macular degeneration, and in further embodiments said administering causes a reduction in said symptom and ii) a composition comprising compounds disclosed herein or salt thereof and substituted and unsubstituted derivatives thereof functioning to decrease choroidal neovascularization and 2) administering said compound to said subject.
• said eye disease is age-related macular degeneration
• said subject is a human.
• said administration is topically to the eye.
• said salt is a hydrochloride salt.
• said composition is a liquid solution.
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject that exhibits a symptom of macular degeneration, and in further embodiments said administering causes a reduction in said symptom and ii) a composition comprising tetramethylpyrazine or salt thereof and 2) administering said compound to said subject.
• said macular degeneration is age-related.
• said subject is a human.
• said administration is topically to the eye.
• said salt is a hydrochloride salt.
• said composition is a liquid solution.
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject diagnosed or at risk for macular degeneration and ii) a composition comprising tetramethylpyrazine or salt thereof and 2) administering said compound to said subject.
• said macular degeneration is age-related.
• said subject is a human.
• said administration is topically to the eye.
• said salt is a hydrochloride salt.
• said composition is a liquid solution.
• the invention relates to a method of treating or preventing an eye disease comprising: 1) providing i) a subject and ii) a composition comprising agent or salt thereof and 2) administering said compound to said subject.
• said eye disease is macular degeneration.
• said subject is a human.
• said administration is topically to the eye.
• said salt is a hydrochloride salt, hi further embodiments, said composition is a liquid solution.
• said agent composition is greater than 50%, 55 %, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, 99.5% or 99.9% by weight of an isomeric component.
• the subject is diagnosed or at risk for macular degeneration, hi further embodiments, said subject exhibits a symptom of macular degeneration, and in further embodiments said administering causes a reduction in said symptom [0021]
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject diagnosed with or at risk for macular degeneration and ii) a composition comprising timolol or salt thereof and 2) administering said compound to said subject.
• said macular degeneration is age-related.
• said subject is a human.
• said administration is topically to the eye.
• said salt is a hydrochloride salt.
• said composition is a liquid solution.
• said timolol composition is greater than 50%, 55 %, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, 99.5% or 99.9% by weight of a D-timolol component.
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject that exhibits a symptom of macular degeneration, and ⁇ i further embodiments said administering causes a reduction in said symptom and ii) a composition comprising timolol or salt thereof and 2) administering said compound to said subject.
• said macular degeneration is age-related.
• said subject is a human.
• said administration is topically to the eye.
• said salt is a hydrochloride salt, hi further embodiments, said composition is a liquid solution.
• said timolol composition is greater than 50%, 55 %, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, 99.5% or 99.9% by weight of a D-timolol component.
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject diagnosed with or at risk for macular degeneration and ii) a composition comprising a substituted or unsubstituted compound of the following formula:
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject that exhibits a symptom of macular degeneration, and in further embodiments said administering causes a reduction in said symptom and ii) a composition comprising a substituted or unsubstituted compound of the following fo ⁇ nula:
• [0028] or salt thereof functioning to decrease choroidal neovascularization and 2) administering said compound to said subject.
• the invention relates to a method of treating or preventin macular degeneration comprising: 1) providing i) a subject diagnosed with or at risk for macular degeneration and ii) a composition comprising hydralazine or salt thereof and 2) administering said compound to said subject.
• said macular degeneration is age-related.
• said subject is a human.
• said administration is topically to the eye.
• said salt is selected from the group consisting of a hydrochloride salt, hydrochlorothiazide salt or isosorbide dinitrate salt.
• said composition is a liquid solution.
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject that exhibits a symptom of macular degeneration, and in further embodiments said administering causes a reduction in said symptom and ii) a composition comprising hydralazine or salt thereof and 2) administering said compound to said subject.
• said macular degeneration is age-related.
• said subject is a human.
• said administration is topically to the eye.
• said salt is selected from the group consisting of a hydrochloride salt, hydrochlorothiazide salt or isosorbide dinitrate salt.
• said composition is a liquid solution.
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject a subject diagnosed with or at risk for macular degeneration and ii) a composition comprising a substituted or unsubstituted compound of the following formula:
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject a subject that exhibits a symptom of macular degeneration, and in further embodiments said administering causes a reduction in said symptom and ii) a composition comprising a substituted or unsubstituted compound of the following formula:
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject diagnosed with or at risk for macular degeneration and ii) a composition comprising guanabenz or salt thereof and 2) administering said compound to said subject,
• macular degeneration is age-related.
• said subject is a human.
• said administration is topically to the eye.
• said salt is selected from the group of a hydrochloride salt and an acetate salt, hi further embodiments, said composition is a liquid solution.
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject that exhibits a symptom of macular degeneration, and in further embodiments said administering causes a reduction in said symptom and ii) a composition comprising guanabenz or salt thereof and 2) administering said compound to said subject.
• macular degeneration is age-related.
• said subject is a human.
• said administration is topically to the eye.
• said salt is selected from the group of a hydrochloride salt and an acetate salt.
• said composition is a liquid solution.
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject diagnosed with or at risk for macular degeneration and ii) a composition comprising a substituted or unsubstituted compound of the following formula:
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject that exhibits a symptom of macular degeneration, and in further embodiments said administering causes a reduction in said symptom and ii) a composition comprising a substituted or unsubstituted compound of the following formula:
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject a subject diagnosed with or at risk for macular degeneration and ii) a composition comprising a compound having the following structure:
• R 1 is hydrogen, alkyl, aryl, or arylalkyl
• R 2 and R 3 are the same or different and, at each occurrence, independently hydrogen, alkyl, or alkylcarboxyl
• R 2 and R 3 together form a five membered lactone ring
• R 4 is hydrogen or alkyl
• R 5 is alkyl
• said macular degeneration is age-related.
• said subject is a human.
• said administration is topically to the eye.
• said salt is a hydrochloride salt.
• said composition is a liquid solution.
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject a subject that exhibits a symptom of macular degeneration, and in further embodiments said administering causes a reduction in said symptom and ii) a composition comprising a compound having the following structure:
• R 1 is hydrogen, alkyl, aryl, or arylalkyl
• R 2 and R 3 are the same or different and, at each occurrence, independently hydrogen, alkyl, or alkylcarboxyl
• R 2 and R 3 together form a five membered lactone ring
• R 4 is hydrogen or alkyl
• R 5 is alkyl
• said macular degeneration is age-related.
• said subject is a human.
• said administration is topically to the eye.
• said salt is a hydrochloride salt.
• said composition is a liquid solution.
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject diagnosed with or at risk for macular degeneration and ii) a composition comprising a substituted or unsubstituted compound of the following formula:
• R 1 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl
• R 2 and R 3 are the same or different and, at each occurrence, independently hydrogen, alkyl, substituted alkyl, alkylcarboxyl or substituted alkylcarboxyl; or R 2 and R 3 together and the carbon to which they are attached form a substituted or unsubstituted five membered lactone
• R 4 is hydrogen, alkyl or substituted alkyl
• R 5 is hydrogen, alkyl or substituted alkyl; 2) administering said compound to said subject.
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject that exhibits a symptom of macular degeneration, and in further embodiments said administering causes a reduction in said symptom and ii) a composition comprising a substituted or unsubstituted compound of the following formula:
• R 1 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl
• R 2 and R 3 are the same or different and, at each occurrence, independently ny ⁇ rogen, alkyl, substituted alkyl, alkylcarboxyl or substituted alkylcarboxyl; or R 2 and R 3 together and the carbon to which they are attached form a substituted or unsubstituted five membered lactone
• R 4 is hydrogen, alkyl or substituted alkyl
• R 5 is hydrogen, alkyl or substituted alkyl; 2) administering said compound to said subject.
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject diagnosed with or at risk for macular degeneration and ii) a composition comprising a compound having the following structure:
• said macular degeneration is age- related.
• said subject is a human.
• said administration is topically to the eye.
• said salt is a hydrochloride salt.
• said composition is a liquid solution.
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject that exhibits a symptom of macular degeneration, and in further embodiments said administering causes a reduction in said symptom and ii) a composition comprising a compound having the following structure:
• said macular degeneration is age- related.
• said subject is a human.
• said administration is topically to the eye.
• said salt is a hydrochloride salt.
• said composition is a liquid solution.
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject diagnosed with or at risk for macular degeneration and ii) a composition comprising a substituted or unsubstituted compound having the following structure:
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject that exhibits a symptom of macular degeneration, and in further embodiments said administering causes a reduction in said symptom and ii) a composition comprising a substituted or unsubstituted compound having the following structure:
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject diagnosed with or at risk for macular degeneration and ii) a composition comprising flavon and 2) administering said compound to said subject, hi further embodiments, said macular degeneration is age-related.
• said subject is a human.
• said administration is topically to the eye.
• said composition is a liquid solution.
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject that exhibits a symptom of macular degeneration, and in further embodiments said administering causes a reduction in said symptom and ii) a composition comprising flavon and 2) administering said compound to said subject.
• said macular degeneration is age-related.
• said subject is a human.
• said administration is topically to the eye.
• said composition is a liquid solution.
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject diagnosed with or at risk for macular degeneration and ii) a composition comprising a substituted or unsubstituted compound of the following formula:
• said substituted compound is quercetin, apigenin or puerarin.
• said subject is a human.
• said administration is topically to the eye.
• said composition is a liquid solution.
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject that exhibits a symptom of macular degeneration, and in further embodiments said administering causes a reduction in said symptom and ii) a composition comprising a substituted or unsubstituted compound of the following formula:
• said substituted compound is quercetin, apigenin or puerarin.
• said subject is a human.
• said administration is topically to the eye.
• said composition is a liquid solution.
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject diagnosed with or at risk for macular degeneration and ii) a composition comprising prednisolone and salts thereof and 2) administering said compound to said subject.
• said macular degeneration is age-related.
• said subject is a human.
• said administration is topically to the eye.
• said composition is a liquid solution.
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject that exhibits a symptom of macular degeneration, and in further embodiments said administering causes a reduction in said symptom and ii) a composition comprising prednisolone and salts thereof and 2) administering said compound to said subject.
• said macular degeneration is age-related.
• said subject is a human.
• said administration is topically to the eye.
• said composition is a liquid solution.
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject diagnosed with or at risk for macular degeneration and ii) a composition comprising a substituted or unsubstituted compound of the following formula:
• said salt is a sodium salt.
• said compound is prednisolone, prednisolone acetate, prednisolone sodium phosphate, prednisolone tebutate, prednisone, methylprednisolone, methylprednisolone acetate, or methylprednisolone sodium succinate.
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject that exhibits a symptom of macular degeneration, and in further embodiments said administering causes a reduction in said symptom and H) a composition comprising a substituted or unsubstituted compound of the following formula:
• said salt is a sodium salt.
• said compound is prednisolone, prednisolone acetate, prednisolone sodium phosphate, prednisolone tebutate, prednisone, methylprednisolone, methylprednisolone acetate, or methylprednisolone sodium succinate.
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject diagnosed with or at risk for macular degeneration and ii) a composition comprising a compound having the formula:
• R 2 is hydrogen, nitro, allcyl or halogen
• R 3 is hydrogen or alky
• R 4 is hydroxyl, -NHOMe, or
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject that exhibits a symptom of macular degeneration, and in further embodiments said administering causes a reduction in said symptom and ii) a composition comprising a compound having the formula:
• R 2 is hydrogen, nitro, alkyl or halogen
• R 3 is hydrogen or alky
• R 4 is hydroxyl, -NHOMe, or
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject diagnosed with or at risk for macular degeneration and ii) a composition comprising a substituted or unsubstituted a compound having the formula:
• R 2 is hydrogen, nitro, alkyl or halogen
• R 3 is hydrogen or alky
• R 4 is hydroxyl, -NHOMe, or
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject that exhibits a symptom of macular degeneration, and in further embodiments said administering causes a reduction in said symptom and ii) a composition comprising a substituted or unsubstituted a compound having the formula;
• R 2 is hydrogen, nitro, alkyl or halogen
• R 3 is hydrogen or alky
• R 4 is hydroxyl, -NHOMe, or
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject diagnosed with or at risk for macular degeneration and ii) a composition comprising a substituted or unsubstituted a compound having the formula:
• B is N or C-R 2
• R 2 is hydrogen, nitro, alkyl or halogen
• R 3 is hydrogen, nitro, -CO 2 H, or alky
• R 4 is hydroxyl, - NHOMe, or
• A is C-H or N, and R 5 is hydrogen, -CH 2 CO 2 H, or nitro.
• R 3 is nitro and R 5 is hydrogen.
• B is C-R 2 wherein R 2 is nitro and R 5 is hydrogen.
• R 1 is nitro and R 5 is hydrogen and R 3 is -CO 2 H or salt thereof functioning to decrease choroidal neovascularization; and 2) administering said compound to said subject.
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject that exhibits a symptom of macular degeneration, and in further embodiments said administering causes a reduction in said symptom and ii) a composition comprising a substituted or unsubstituted a compound having the formula:
• B is N or C-R 2
• R 2 is hydrogen, nitro, alkyl or halogen
• R 3 is hydrogen, nitro, -CO 2 H, or alky
• R is hydroxyl, - NHOMe, or
• A is C-H or N, and R 5 is hydrogen, -CH 2 CO 2 H, or nitro.
• R 3 is nitro and R 5 is hydrogen.
• B is C-R 2 wherein R is nitro and R is hydrogen.
• R is nitro and R 5 is hydrogen and R 3 is -CO 2 H or salt thereof functioning to decrease choroidal neovascularization; and 2) administering said compound to said subject.
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject diagnosed with or at risk for macular degeneration and ii) a composition comprising a substituted or unsubstituted compound having the formula:
• said macular degeneration is age-related.
• said subject is a human.
• said administration is topically to the eye.
• said composition is a liquid solution,
• said subject is diagnosed with macular degeneration.
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject that exhibits a symptom of macular degeneration, and in further embodiments said administering causes a reduction in said symptom and ii) a composition comprising a substituted or unsubstituted compound having the formula:
• said macular degeneration is age-related.
• said subject is a human, hi further embodiments, said administration is topically to the eye.
• said composition is a liquid solution.
• said subject is diagnosed with macular degeneration.
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject diagnosed with or at risk for macular degeneration and ii) a composition comprising a substituted or unsubstituted compound having the formula:
• said macular degeneration is age-related.
• said subject is a human.
• said administration is topically to the eye.
• said composition is a liquid solution, hi further embodiments, said subject is diagnosed with macular degeneration.
• the invention relates to a method of treating or preventing macular degeneration comprising: 1) providing i) a subject that exhibits a symptom of macular degeneration, and in further embodiments said administering causes a reduction in said symptom and ii) a composition comprising a substituted or unsubstituted compound having the formula:
• said macular degeneration is age-related.
• said subject is a human.
• said administration is topically to the eye.
• said composition is a liquid solution.
• said subject is diagnosed with macular degeneration.
• the invention relates to a method of managing, prevention, and/or treating age-related macular degeneration comprising: 1) providing i) a subject and ii) a composition comprising a compound functioning to decrease choroidal neovascularization and 2) administering said compound to said subject.
• said compound is an interleukin-1 (IL-I) blockers preferably CK-17 (5- bromo-5-methyl-3-phenyl-2-phenylimino-l,3-thiazinan-4-one), CK-112, CK-113, CK- 115, CK-116, and CK-117.
• said compound is a substituted or unsubstituted compound or derivative of the following structure:
• said compound has the following structure:
• R 1 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl
• R 2 and R 3 are the same or different and, at each occurrence, independently hydrogen, alkyl, substituted alkyl, alkylcarboxyl or substituted alkylcarboxyl
• R 4 is hydrogen or alkyl
• R 5 is alkyl
• said compound is selected from the group consisting hydralazine i.e., phthalazin-1-ylhydrazine, quanabenz, i.e., (2-[(2,6- dichlorophenyl)methylideneamino] guanidine, D-timolol, i.e., (2R)-l-[(4-morpholin-4- yl-l,2,5-thiadiazol-3-yl)oxy]-3-(tert-butylamino)propan-2-ol, apigenin i.e., 4,5- dihydiOxy-2-(4-hydiOxyphenyl)chromen-7-one, naringenin, i.e., 5,7-dihydroxy-2-(4- hydroxyphenyl)chiOman-4-one, quercetin, i.e., 2-(3,4-dmydiOxyphenyl)-3
• the invention relates to the use of a compound functioning to decrease choroidal neovascularization for the manufacture of a medicament for the treatment of macular degeneration, preferably age-related macular degeneration.
• the invention relates to a compound or derivative of a compound herein functioning as an inter leukin-1 blocker used in the treatment or prevention of eye diseases.
• said interleutkin-1 blocker is selected from the group consisting of CK-17, CK-112, CK-113, CK-115, CK-116, and CK-117.
• said compound is prednisolone.
• said compound is a substituted or unsubstituted compound or derivative of the following structure:
• said compound has the following structure:
• R 1 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl
• R 2 and R 3 are the same or different and, at each occurrence, independently hydrogen, alkyl, substituted alkyl, alkylcarboxyl or substituted alkylcarboxyl
• R 4 is hydrogen or alkyl
• R 5 is alkyl.
• the invention relates to the use of substituted or unsubstituted compounds disclosed herein or derivatives thereof for the treatment of age- related macular degeneration.
• the present invention provides methods of treating or preventing eye disease comprising administering an IL-I blocker to a patient with eye- disease such that at least one symptom of the eye disease is reduced or eliminated.
• the eye disease is age-related macular degeneration.
• the administering is performed via the eye.
• the administering is performed orally or systemically.
• the subject is diagnosed or at risk for macular degeneration.
• compositions comprising; i) an IL-I blocker, and ii) an ophthalmic solution.
• the present invention provides systems comprising: a) a composition comprising an IL-I blocker and an ophthalmic solution; and b) an eye-dropper.
• the composition is located in the eye- dropper.
• the IL-blocker is specific for IL-I alpha. In other embodiments, the IL-blocker is specific for IL-I beta. In further embodiments, the IL-I blocker is selected from the group consisting of CK- 17, CK-112, CK-113, CK-115, CK- 116, CK-117, CK-IOlA, CK-103A, CK-119, CK-120, and CK- 122, and similar compounds.
• the IL-I blocker is selected from the group consisting of: IL-I siRNA sequences configured to reduce the expression of IL-I proteins, a vector configured to express IL-I siRNA sequences, anti-IL-1 antibodies or fragments, anti-ILl antisense sequences, and vectors configured to express anti-ILl antisense sequences.
• the invention relates to a method of treating or preventing age-related macular degeneration comprising: 1) providing i) a subject diagnosed or at risk for macular degeneration and ii) a composition comprising a compound functioning to decrease choroidal neovascularization and 2) administering said compound to said subject.
• said compound is an interleukin-1 blocker.
• said compound is selected from the group consisting of CK-17, CK-112, CK-113, CK-115, CK-116, CK-117, CK-IOlA, CK-103A, CK-119, CK- 120, and CK- 122.
• said compound is prednisolone.
• the invention relates to the use of a compound functioning to decrease choroidal neovascularization for the manufacture of a medicament for the treatment of macular degeneration.
• a compound functioning to decrease choroidal neovascularization for the manufacture of a medicament for the treatment of macular degeneration.
• macular degeneration Preferably age-related macular degeneration.
• the invention relates to the use of compound disclosed herein for the manufacture of a medicament for the treatment of age-related macular degeneration.
• age-related macular degeneration Preferably age-related macular degeneration.
• the invention relates to the use of a substituted compound disclosed herein functioning to decrease choroidal neovascularization for the manufacture of a medicament for the treatment of age-related macular degeneration.
• said compound is an interleukin-1 blocker.
• said compound is selected from the group consisting of CK-17, CK-112, CK-113, CK-115, CK-116, CK-117, CK-101A, CK-103A, CK-119, CK-120, and CK- 122.
• said compound is prednisolone, tetrandrine or osthole or derivative or substituted compound thereof, hi further embodiments, said compound is a substituted or unsubstituted compound or derivative of the following structure:
• the invention relates to the use of a compounds disclosed herein functioning to inhibit IL-I induced uveitis for the manufacture of a medicament for the treatment of arthritis, preferably rheumatoid arthritis.
• a subject shows symptoms of arthritis before administration
• said compound is an interleukin-1 blocker.
• said compound is selected from the group consisting of CK-17, CK-112, CK-113, CK-115, CK-116, CK-117, CK-IOlA, CK-103A, CK-119, CK-120, and CK-122.
• said compound is prednisolone, tetrandrine or osthole or derivative or substituted compound thereof.
• compositions comprising the active compounds of the present invention may include nutritional/dietary supplements and bulk-drug compositions useful in the manufacture of pharmaceutical compositions (e.g., impure or non-sterile compositions) and pharmaceutical compositions (i.e., compositions that are suitable for administration to a subject) that can be used in the preparation of unit dosage forms.
• Such compositions optionally comprise a prophylactically or therapeutically effective amount of a prophylactic and/or therapeutic agent disclosed herein or a combination of those agents and a pharmaceutically acceptable carrier.
• compositions of the invention comprise a prophylactically or therapeutically effective amount of the active compound and another therapeutic or prophylactic agent, and a pharmaceutically acceptable carrier. These compositions may contain between 0.1 - 99 % of the active ingredient.
• the therapeutic compounds are in an ophthalmic solution (e.g. such that the blockers can be administered directly to the eye of the patient via an eye dropper).
• the osmotic value of the solution is about 0.9% sodium chloride (e.g. 0.6% to about 1%).
• the ophthalmic solution have a pH of about 7.4 (e.g. 6.6 to 7.8, preferably 7.0 to 7.4). It is also preferred that the ophthalmic solution be buffered to prevent wide changes in the pH.
• Figure 1 is a fluorescein angiograph that shows the control formation of choroidal neovascularization (CNV) by using a laser treatment.
• Figure 2 is a fluorescein angiograph that shows the inhibition of CNV formation by intraperitonal administration of 3 mg/kg 10 mg/kg hydralazine.
• Figure 3 is a fluorescein angiograph that shows the inhibition of CNV formation by intraperitonal administration of 20 mg/kg guanabenz.
• Figure 4 is a fluorescein angiograph that shows the inhibition of CNV formation by intraperitonal administration of 3 mg/kg prednisolone,
• Figure 5 is a fluorescein angiograph that shows the inhibition of CNV formation by intraperitonal administration of 30 mg/kg CK-17.
• Figure 6 is a fluorescein angiograph that shows the inhibition of CNV formation by intraperitonal administration of 10 mg/kg CK-112.
• Figure 7 is a fluorescein angiograph that shows the inhibition of CNV formation by intraperitonal administration of 30 mg/kg CK-112.
• Figure 8 is a fluorescein angiograph that shows the inhibition of CNV formation by intraperitonal administration of 30 mg/kg CK-113.
• Figure 9 is a fluorescein angiograph that shows the inhibition of CNV formation by intraperitonal administration of 10 mg/kg CK-115.
• Figure 10 is a fluorescein angiograph that shows the inhibition of CNV formation by intraperitonal administration of 10 mg/kg CK-116.
• Figure 11 is a fluorescein angiograph that shows the inhibition of CNV formation by intraperitonal administration of 10 mg/kg CK-117.
• Figure 12 shows data of blockade of IL-I Induced Uveitis by Synthetic IL-
• Figure 13 show data of blockade of IL-I Induced Uveitis by Natural
• Figure 17 shows the chemical structures of CK-17, CK-112, CK-113, CK-
• Figure 18 shows the chemical structures of CK-IOlA, CK-103A, CK-119,
• Figure 19 shows the chemical structures of DN-4 through DN- 15.
• Figure 20 shows the chemical structures of DC-I through DC- 17.
• the present invention relates in general to therapeutic compositions and methods of use.
• the invention relates to the field of eye health, hi some embodiments, the invention relates to the prevention and treatment of macular degeneration by administering compounds disclosed herein. hi some embodiments, the invention relates to compositions and methods of improving vision.
• the invention relates to the prevention and treatment of age-related macular degeneration by administering compounds disclosed herein.
• the invention relates to compositions and methods of improving health including dietary supplements that prevent of choroid ischemic trauma leading to age-related macular degeneration.
• Numerous methods have been attempted to treat age-related macular degeneration without success. They include laser photocoagulation for choroidal neovascularization, radiation treatment, transpupillary thermotherapy of subfoveal occult choroidal neovascularization, submacular surgery, limited macular translocation, adjuncts in surgery, argon laser to drusen, infrared diode laser photocoagulation.
• VEGF vascular endothelial growth factor
• PEDF pigment epithelium-derived factor
• angiostatin angiostatin
• an "eye disease” means any variety of diseases, impairments, or defects that cause, vision loss, blurred or decreased central close-up and distance vision, blind spots, objects to appear a different color or shape, neuro- ophthalmic manifestations of vascular eye diseases, including ischemic optic neuropathy, anterior ischemic optic neuropathy, retinal artery occlusion, asymptomatic retinal emboli, asymptomatic retinal embolus or ischemia of retinal tissue, retinal edema, amaurosis fugax, reduction in visual field, occlusion of ocular vessels, stagnation of blood flow within the arteriole, cataracts, glaucoma, proptosis, eyelid retraction, restrictive myopathy, diplopia (double vision), compressive optic neuropathy, and/or exposure keratopathy.
• the eye disease is macular degeneration or diabetic eye disease. It is not intended that the present invention be limited to treating any particular underlying disease resulting in vision defects or impairments.
• macular degeneration means any condition that causes part of the macula to deteriorate. This degeneration may be partial or total, and it is not intended to be limited to advance stages of the disease: thus, is intended to include a subject that is diagnosed with drusen even thought the subject does not have any symptoms of impaired vision.
• a symptom of macular degeneration is a change in central vision. The patient may notice blurred central vision or a blank spot on the page when reading. The patient may notice visual distortion such as bending of straight lines. Images may appear smaller. Some patients notice a change in color perception and some experience abnormal light sensations. These symptoms may come on suddenly and become progressively more troublesome. Sudden onset of symptoms, particularly vision distortion, is an indication for immediate evaluation by an ophthalmologist.
• a diagnosis of macular degeneration means any analysis of macular changes or function in a subject. It is not intended to be limited to any particular method.
• an eye examiner e.g., doctor
• the eye examiner may also administer a visual field test, looking for blank spots in the central vision.
• the examiner may call for fluorescein angiography (intravenous injection of fluorescent dye followed by visual examination and photography of the back of the eye) to determine if blood vessels in the retina are leaking.
• Some risk factors for having macular degeneration include, age, smoking, and a diet that is rich in saturated fat. Others may be at risk for macular degeneration because of genetic heritage or environmental exposure.
• the invention relates to treating or prevention of age-related macular degeneration, preferably prophylactic prevention and treatment.
• Age-related macular degeneration may be characterized as a dry (atrophic) or wet (exudative) form. Multiple, small, round, yellow-white spots called drusen are identifiers for the dry type. The spots are typically located in the back of the eye at the level of the outer retina. Subjects with these spots may have excellent vision and no symptoms. Most subjects with age-related macular degeneration begin with the dry form. In the wet form, newly created abnormal blood vessels grow under the center of the retina. These blood vessels leak, bleed, and scar the retina, distorting vision or destroying central vision. Vision distortion may starts in one eye and may affect the other eye later.
• a diabetic (Type I or Type II) patient is at risk for macular degeneration.
• Diabetic macular degeneration is the deterioration of the macula due to diabetes. Cystoid macular degeneration is the loss of vision in the macula due to fluid-filled areas (cysts) in the macular region. This may be a result of other disorders, inflammation, or high myopia.
• a compound "functioning to decrease choroidal neovascularization” means that a statistically significant reduction of choroidal neovascularization can be measured, e.g. by fluorescein angiography, after some period of time of administering said compound to a mammalian after physical disruption of the eye's Bruch's membrane, e.g., via a laser.
• fluorescein angiography after some period of time of administering said compound to a mammalian after physical disruption of the eye's Bruch's membrane, e.g., via a laser.
• “Isomers” means any of two or more substances that are composed of the same elements in the same proportions but differ in the three dimensional arrangement of atoms including enantiomeric (i.e., mirror images) and diastereomeric isomers.
• Timolol compound or molecules, and the like means substituted or unsubstituted compounds of the following formula:
• timolol component refers that part of a composition that contains all of timolol molecules in a given composition, including all conformational and stereomeric forms.
• a given compound e.g. designated by a structure
• makes up a large percentage e.g. by number of molecules and/or by weight
• a given timolol derivative may be present in an aqueous composition at a level where 70% of all the timolol components are of that given compound, e.g. D-Timolol, while most of the composition itself is composed of water.
• salts refers to any salt that complexes with identified compounds contained herein while retaining a desired function, e.g., biological activity.
• salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g.
• hydrochloric acid hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like
• organic acids such as, but not limited to, acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic, acid, naphthalene sulfonic acid, naphthalene disulfonic acid, and polygalacturonic acid.
• Salt compounds can also be administered as pharmaceutically acceptable quaternary salts known by a person skilled in the art, which specifically include the quaternary ammonium salts of the formula ⁇ NR,R',R" + Z " , wherein R, R', R" is independently hydrogen, alkyl, or benzyl, and Z is a counter ion, including, but not limited to, chloride, bromide, iodide, alkoxide, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandeloate, and diphenylacetate).
• quaternary ammonium salts of the formula ⁇ NR,R',R" + Z " , wherein R, R', R" is independently hydrogen, alkyl, or benzy
• Adverse drug reaction means any response to a drug that is noxious and unintended and occurs in doses for prophylaxis, diagnosis, or therapy including side effects, toxicity, hypersensitivity, drug interactions, complications, or other idiosyncrasy. Side effects are often adverse symptom produced by a therapeutic serum level of drug produced by its pharmacological effect on unintended organ systems (e.g., blurred vision from anticholinergic antihistamine). A toxic side effect is an adverse symptom or other effect produced by an excessive or prolonged chemical exposure to a drug (e.g., digitalis toxicity, liver toxicity). Hypersensitivities are immune-mediated adverse reactions (e.g., anaphylaxis, allergy).
• Drug interactions are adverse effects arising from interactions with other drugs, foods or disease states (e.g., warfarin and erythromycin, cisapride and grapefruit, loperamide and Clostridium difficile colitis).
• Complications are diseases caused by a drag (e.g., NSAID-induced gastric ulcer, estrogen-induced thrombosis).
• the adverse drag reaction may be mediated by known or unknown mechanisms (e.g., Agranulocytosis associated with chloramphenicol or clozapine). Such adverse drag reaction can be determined by subject observation, assay or animal model well-known in the art.
• Alkyl means a straight chain or branched, noncyclic or cyclic, unsaturated or saturated aliphatic hydrocarbon containing from 1 to 10 carbon atoms, while the term “lower alkyl” has the same meaning as alkyl but contains from 1 to 6 carbon atoms. The term “higher alkyl” has the same meaning as alkyl but contains from 2 to 10 carbon atoms.
• saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-septyl, n-octyl, n-nonyl, and the like; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like.
• saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; while unsaturated cyclic alkyls include cyclopentenyl and cyclohexenyl, and the like.
• Cyclic alkyls are also referred to herein as a "homocycles” or “homocyclic rings.”
• Unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (referred to as an "alkenyl” or “alkynyl", respectively).
• Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-l- butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, and the like; while representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3 -methyl- 1-butynyl, and the like.
• Alkylamino and dialkylamino mean one or two alkyl moiety attached through a nitrogen bridge (i.e., --N-alkyl) such as methylamino, ethylarnino, dimethylamino, diethylamino, and the like.
• Alkylcarboxyl means an alkyl moiety attached through a carboxyl group
• Alkylcarbonyl means an alkyl moiety attached through a carbonyl group
• Alkylthiol means an alkyl moiety attached through a sulfur bridge (i.e., -
• Alkyloxy means an alkyl moiety attached through an oxygen bridge
• Alkoxide means an alkyl moiety attached to a negatively charged oxygen atom (i.e., O alkyl) such as methoxide or ethoxide.
• an "amine” group means -NH 2
• “ammonia” means the gas NH 3 .
• Aryl means an aromatic carbocyclic moiety such as phenyl or naphthyl.
• Arylalkyl means an aryl moiety attached through an alkyl bridge (e.g., -
• Aryloxy means an aryl moiety attached through an oxygen bridge (i.e., -
• Arylthio means an alkyl moiety attached through a sulfur bridge (i.e., -
• Heteroaryl means an aromatic heterocycle ring of 5- to 10 members and having at least one heteroatom selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono- and bicyclic ring systems.
• Representative heteroaryls are furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyiimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl
• Heteroarylalkyl means an alkyl having at least one allcyl hydrogen atom replaced with a heteroaryl moiety, such as -CH 2 pyridinyI, ⁇ CH 2 pyrimidinyl, and the like.
• Heterocycle (also referred to herein as a “heterocyclic ring”) means a 4- to 7-membered monocyclic, or 7- to 10-membered bicyclic, heterocyclic ring which is either saturated, unsaturated, or aromatic, and which contains from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized, including bicyclic rings in which any of the above heterocycles are fused to a benzene ring.
• the heterocycle may be attached via any heteroatom or carbon atom.
• Heterocycles include heteroaryls as defined above.
• heterocycles also include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
• Heterocyclealkyl means an alkyl having at least one alkyl hydrogen atom replaced with a heterocycle, such as --CH 2 morpholinyl, and the like.
• Homocycle (also referred to herein as “homocyclic ring”) means a saturated or unsaturated (but not aromatic) carbocyclic ring containing from 3-7 carbon atoms, such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclohexene, and the like.
• “Isomers” means any of two or more substances that are composed of the same elements in the same proportions but differ in the three dimensional arrangement of atoms including enantiomeric (i.e., mirror images) and diastereomeric isomers,
• the term "derivative" when used in relation to a chemical compound refers to a similar structure that upon application, e.g., administration to a subject, is capable of providing, directly or indirectly, the function said chemical compound is disclosed to have (albeit the derivative may have increased or decreased function).
• substituting one atom for another atom in a chemical compound provides a compound of similar structure, e.g., a carbon atom for a nitrogen atom.
• the compound of similar structure may be capable of functioning to decrease choroidal neovascularization.
• Certain claimed embodiments are intended to encompass minor changes in chemical structure provided that the derivative can decrease choroidal neovascularization.
• a subject when used in connection with a disease or condition means to provide beneficial effects to a subject being administered with a prophylactic or therapeutic agent, which does not result in a cure of the disease.
• a subject is administered with one or more prophylactic or therapeutic agents to manage a disease so as to prevent the progression or worsening of the disease.
• the terms “prevent” and “preventing” include the prevention of the recurrence, spread or onset. It is not intended that the present invention be limited to complete prevention. In some embodiments, the onset is delayed, or the severity of the disease is reduced.
• Subject means any animal, preferably a human patient, livestock, or domestic pet.
• substituted means at least one hydrogen atom of a molecular arrangement is replaced with a substituent.
• Substituents within the context of this invention include, but are not limited to, halogen, hydroxy, oxo, cyano, nitro, amino, alkylamino, dialkylamino, alkyl, alkoxy, alkylthio, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, and heterocyclealkyl, as well as, --NR 8 R b , --NR 3 C(O)R b , — NR a C(O)NR a NR b , --NR 8 C(O)ORb ⁇ NR a SO 2 R bj -C(K ) )R 11 , C(O)OR 2 , - C(O)NRJRh, -OC(O)NRJRb, -OR 9 , -SR 4 , ⁇ SOR a , --S(
• substituents may be further substituted with one or more of the above substituents, such that the substituent comprises a substituted alky, substituted aryl, substituted arylalkyl, substituted heterocycle, or substituted heterocyclealkyl.
• R a and R b in this context may be the same or different and, independently, hydrogen, alkyl, haloalkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl.
• unsubstituted refers to any compound does not contain extra substituents attached to the compound.
• An unsubstituted compound refers to the chemical makeup of the compound without extra substituents, e.g., the compound does not contain protecting grou ⁇ (s).
• unsubstituted proline is a proline amino acid even though the amino group of proline may be considered disubstituted with alkyl groups.
• a chemical structure may be drawn with two lines between a first atom and substituent meaning that there are two bonds, i.e., designate a double between the first atom and a defined substituent or it may designate two single bonds between the first atom and two defined substituent atoms.
• the terms “treat” and “treating” are not limited to the case where the subject (e.g. patient) is cured and the disease is eradicated. Rather, the present invention also contemplates treatment that merely reduces symptoms, improves vision (to some degree) and/or delays disease progression.
• IL-I blocker refers to any compound or composition that is able to at least partially inhibit the biological activity or expression of IL-Ia and/or IL-Ib in the eye of a patient.
• IL-I blockers bind to IL-I proteins or RNA transcripts.
• IL-I blockers competitively inhibit the activity of IL-I proteins.
• the IL-I blockers destroy IL-I proteins through cleavage.
• the IL-I blockers cleave or bind to IL-I mRNA transcripts.
• IL-I blockers include, but are not limited to, CK- 17 (5-bromo-5-methyl-3-phenyl-2-phenylimino-l,3-thiazinan-4-one), CK-112, CK- 113, CK-115, CK-116, CK-117, IL-I siRNA sequences and vectors expressing IL-I siRNA sequences, IL-I antisense sequences and vectors expressing IL-I antisense sequences, anti-IL-1 antibodies and fragments thereof, including chimeric and preferably humanized or human anti-IL-1 antibodies.
• Nucleic acid based IL-I blockers such as siRNA and antisense can be designed, for example, using the human IL-Ia sequence (accession no. BC013142) or the human IL-Ib sequence (accession number BC008678) using techniques and software that are known in the art.
• Antibody based IL-I blockers such as anti-ILla or anti-ILlb mononclonal antibodies can be generated using the human IL-Ia protein sequence (accession no. CAG33695) or the human IL-Ib protein sequence (accession no. CAG28607) using techniques known in the art.
• siRNAs refers to short interfering RNAs.
• siRNAs comprise a duplex, or double-stranded region, of about 18-25 nucleotides long. Often siRNAs contain from about two to four unpaired nucleotides at the 3' end of each strand. At least one strand of the duplex or double-stranded region of a siRNA is substantially homologous to or substantially complementary to a target RNA molecule, such as IL-I mRNA transcripts.
• siRNAs may also contain additional sequences; non-limiting examples of such sequences include linking sequences, or loops, as well as stem and other folded structures. siRNAs appear to function as key intermediaries in triggering RNA interference in invertebrates and in vertebrates, and in triggering sequence-specific RNA degradation during posttranscriptional gene silencing in plants.
• RNA interference refers to the silencing or decreasing of gene expression by siRNAs. It is the process of sequence-specific, posttranscriptional gene silencing in animals and plants, initiated by siRNA that is homologous in its duplex region to the sequence of the silenced gene.
• the gene e.g. IL- Ia or IL-Ib
• the gene may be endogenous or exogenous to the organism, present integrated into a chromosome or present in a transfection vector that is not integrated into the genome.
• the expression of the gene e.g. IL-Ia
• RNAi may also be considered to inhibit the function of a target IL-I RNA; the function of the target IL-I RNA may be complete or partial.
• Aging is a chronic process to cause degeneration of cells, tissues, and organs, including choroidal blood vessels, retinal pigment epithelium cells (RPEC) and Bruch's membrane of macular. Most notably arteriosclerotic aging changes choroidal blood vessels, particularly the macular chorio-capillaris with a decrease in total capillary membrane and the blood flow. As a result, RPE starts to accumulate lipofuscin, alters cell shape, density, pigmentation, lysosomal activity and extracellular matrix formation. Gradually, Bruch's membrane shows thickening and decreased permeability, resulting with breakdown of Bruch's membrane which allows choroidal neovascularization (CNV) to appear.
• CNV choroidal neovascularization
• AMD preferably is treated at the earliest stage possible to prevent disease progression.
• the earliest stage of AMD development is the malfunction of choroidal blood flow, resulting in a decrease of the blood flow of choriocapillaris. Chain reactions are triggered that lead to RPE degenerations, Bruch's membrane breakdown, CNV formation, AMD and finally blindness. Therefore, specific drugs that increase the choroidal blood flow were found herein to be useful to prevent the AMD from developing and worsening.
• hypotensive agents e.g., timolol, hydralazine guanaben
• fiavonoids e.g., Apigenin, Naringenin Quercetin, Flavon
• N-nitro-pyrazoles and C-nitro-pyrazoles e.g., DN-6, CN-7, DN- 13, and DC-5.
• the term "pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. ' Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
• carrier refers to a diluent, adjuvant, excipient, or vehicle with which the active compound is administered.
• Such pharmaceutical vehicles can be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
• the pharmaceutical vehicles can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like, In addition, auxiliary, stabilizing, thickening, lubricating and coloring agents can be used.
• the pharmaceutically acceptable vehicles are preferably sterile. Water can be the vehicle when the active compound is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid vehicles, particularly for injectable solutions.
• Suitable pharmaceutical vehicles also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propyleneglycol, water, ethanol and the like.
• excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propyleneglycol, water, ethanol and the like.
• the present compositions if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
• compositions can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained- release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use.
• the pharmaceutically acceptable vehicle is a capsule (see e.g., U.S. Pat. No. 5,698,155).
• the active compound and optionally another therapeutic or prophylactic agent are formulated in accordance with routine procedures as pharmaceutical compositions adapted for intravenous administration to human beings.
• the active compound for intravenous administration are solutions in sterile isotonic aqueous buffer.
• the compositions can also include a solubilizing agent,
• Compositions for intravenous administration can optionally include a local anesthetic such as lignocaine to ease pain at the site of the injection.
• the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
• the active compound is to be administered by infusion, it can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline.
• an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.
• compositions for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example.
• Orally administered compositions can contain one or more optional agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen., or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation.
• sweetening agents such as fructose, aspartame or saccharin
• flavoring agents such as peppermint, oil of wintergreen., or cherry
• coloring agents such as peppermint, oil of wintergreen., or cherry
• preserving agents to provide a pharmaceutically palatable preparation.
• the compositions can be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time.
• Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for an orally administered of the active compound.
• fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture.
• delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations.
• a time delay material such as glycerol monostearate or glycerol stearate can also be used.
• Oral compositions can include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. Such vehicles are preferably of pharmaceutical grade.
• the effect of the active compound can be delayed or prolonged by proper formulation.
• a slowly soluble pellet of the active compound can be prepared and incorporated in a tablet or capsule.
• the technique can be improved by making pellets of several different dissolution rates and filling capsules with a mixture of the pellets. Tablets or capsules can be coated with a film that resists dissolution for a predictable period of time. Even the parenteral preparations can be made long-acting, by dissolving or suspending the compound in oily or emulsified vehicles which allow it to disperse only slowly in the serum.
• compositions for use in accordance with the present invention can be formulated in conventional manner using one or more physiologically acceptable carriers or excipients.
• the compound and optionally another therapeutic or prophylactic agent and their physiologically acceptable salts and solvates can be formulated into pharmaceutical compositions for administration by inhalation or insufflation (either through the mouth or the nose) or oral, parenteral or mucosol (such as buccal, vaginal, rectal, sublingual) administration.
• the administration is optical (e.g. eyes drops applied directly to the eye).
• local or systemic parenteral administration is used.
• compositions can take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate).
• binding agents e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
• fillers e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate
• lubricants e.g., magnesium stearate, talc or silica
• disintegrants e.g., potato starch or sodium
• Liquid preparations for oral administration can take the form of, for example, solutions, syrups or suspensions, or they can be presented as a dry product for constitution with water or other suitable vehicle before use.
• Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid).
• the preparations can also contain buffer salts, flavoring, coloring and sweetening agents as appropriate.
• Preparations for oral administration can be suitably formulated to give controlled release of the active compound.
• compositions can take the form of tablets or lozenges formulated in conventional manner.
• compositions for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofiuoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
• a suitable propellant e.g., dichlorodifluoromethane, trichlorofiuoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
• a suitable propellant e.g., dichlorodifluoromethane, trichlorofiuoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
• a suitable propellant e.g., dichlorodifluoromethane, trichlorofiuoromethane, dichlorotetrafluoroethane
• compositions can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
• Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
• the pharmaceutical compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
• the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen- free water, before use.
• compositions can also be fo ⁇ nulated as a depot preparation.
• Such long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
• the pha ⁇ naceutical compositions can be fo ⁇ nulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
• compositions can, if desired, be presented in a pack or dispenser device that can contain one or more unit dosage forms containing the active ingredient.
• the pack can for example comprise metal or plastic foil, such as a blister pack.
• the pack or dispenser device can be accompanied by instructions for administration.
• the pack or dispenser contains one or more unit dosage forms containing no more than the recommended dosage formulation as determined in the Physician 's Desk Reference (56 th ed. 2002, herein incorporated by reference in its entirety).
• Methods of administering the active compound and optionally another therapeutic or prophylactic agent include, but are not limited to, parenteral administration (e.g., intradermal, intramuscular, intraperitoneal, intravenous and subcutaneous), epidural, and mucosal (e.g., intranasal, rectal, vaginal, sublingual, buccal or oral routes).
• parenteral administration e.g., intradermal, intramuscular, intraperitoneal, intravenous and subcutaneous
• epidural e.g., epidural, and mucosal (e.g., intranasal, rectal, vaginal, sublingual, buccal or oral routes).
• the active compound and optionally another prophylactic or therapeutic agents are administered intramuscularly, intravenously, or subcutaneously.
• the active compound and optionally another prophylactic or therapeutic agent can also be administered by infusion or bolus injection and can be administered together with other biologically active agents. Administration can be local or systemic.
• the active compound and optionally the prophylactic or therapeutic agent and their physiologically acceptable salts and solvates can also be administered by inhalation or insufflation (either through the mouth or the nose). In a preferred embodiment, local or systemic parenteral administration is used.
• administering can be desirable to administer the active compound locally to the area in need of treatment.
• This can be achieved, for example, and not by way of limitation, by local infusion during surgery or topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as silastic membranes, or fibers.
• administration can be by direct injection at the site (or former site) of an atherosclerotic plaque tissue.
• Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon or synthetic pulmonary surfactant.
• the active compound can be formulated as a suppository, with traditional binders and vehicles such as triglycerides.
• the active compound can be delivered in a vesicle, in particular a liposome.
• the active compound can be delivered in a controlled release system.
• a pump can be used.
• polymeric materials can be used.
• the amount of the active compound that is effective in the treatment or prevention of age-related macular degeneration can be determined by standard research techniques.
• the dosage of the active compound which will be effective in the treatment or prevention of age-related macular degeneration can be determined by administering the active compound to an animal in a model such as, e.g., the animal models known to those skilled in the art.
• in vitro assays can optionally be employed to help identify optimal dosage ranges.
• Selection of a particular effective dose can be determined (e.g., via clinical trials) by a skilled artisan based upon the consideration of several factors which will be known to one skilled in the art. Such factors include the disease to be treated or prevented, the symptoms involved, the subject's body mass, the subject's immune status and other factors known by the skilled artisan.
• the dose of the active compound to be administered to a subject is rather widely variable and can be subject to independent judgment. It is often practical to administer the daily dose of the active compound at various hours of the day. However, in any given case, the amount of the active compound administered will depend on such factors as the solubility of the active component, the formulation used, subject condition (such as weight), and/or the route of administration.
• the general range of effective amounts of the active compound alone or in combination with another prophylactic or therapeutic agent(s) are from about 0.001 mg/day to about 1000 mg/day, more preferably from about 0.001 mg/day to 750 mg/day, more preferably from about 0.001 mg/day to 500 mg/day, more preferably from about 0.001 mg/day to 250 mg/day, more preferably from about 0.001 mg/day to 100 mg/day, more preferably from about 0.001 mg/day to 75 mg/day, more preferably from about 0.001 mg/day to 50 mg/day, more preferably from about 0.001 mg/day to 25 mg/day, more preferably from about 0.001 mg/day to 10 mg/day, more preferably from about 0.001 mg/day to 1 mg/day.
• the amount of compound administered will depend on such factors as the solubility of the active component, the formulation used, subject condition (such as weight), and/or the route of administration.
• Naringenin is a flavon analog with potent effects to increase the choroidal blood flow as can be seen in Table 1.
• the blood flow increased rapidly at 30 min after drug administration.
• the effect peaked at 60 min after drug administration and maintained the drug action for at least 2 hrs.
• the choroidal blood flow was increased more than 200% of the original blood flow.
• Apigenin is a flavon analog. The drug actions lasted from 1 hr to 2 hrs after administration (Table 1).
• Puerarin is also a flavon analog similar to apigenin. Puerarin's action started from 1 hr after administration and lasted beyond 3 hrs after administration (Table 1). [00261]
• N-Nitro ⁇ yrazoles including DN-6, DN-7, DN- 12, and DN- 13 showed very strong increase of choroidal blood flow and long duration of action lasting beyond 3 hrs after drug administration (Table 2).
• DN-13 was particularly good as it acted rapidly to increase choroidal blood flow at 30 min after drug administration and the action lasted more than 3 hrs after drug administration (Table 2).
• DC-5 showed the most promising actions with short latent period of less than 30 min and long duration of action lasting longer than 3 hrs (Table 2).
• Table 2 Effects N-nitro razoles and C-n tro yrazoles on Choroidal Blood Flow
• N-Nitropyrazoles and C-nytropyrazoles also showed strong retinal function recovery after ischemic insult (Table 4).
• N-nitropyrazoles were more potent than C-nitropyrazoles to facilitate/enhance retinal function recovery after ischemic insult, except DC-5 which showed stronger effects than any other N-nitropyrazoles to facilitate the retinal function recovery after ischemic insult (Table 4).
• a number of agents which can improve choroidal blood flow were administered intraperitoneally once a day for 4 weeks.
• the first type of agents tested were hypotensive agents including hydralazine, guanabenz, and D-Timolol.
• Hydralazine at 10 mg/kg inhibited all CNV formation effectively.
• the dose of hydralazine was reduced to 5 mg/kg, only four out of eight CNV formation were clearly inhibited as compared to the control.
• Guanabenz was equally effective at 20 mg/kg i.p. All eight CNV formations were inhibited by guanabenz as compared to the control.
• D-Timolol at 15 mg/kg i.p. was effective in inhibiting some CNV formation but not as potent as hydralazine or guanabenz.
• flavonoids including but not limited to apigenin, naringenin, quercetin, and flavon.
• Apigenin at 30 mg/kg i.p. showed a potent inhibition on at least six out of eight CNV formations.
• Naringenin (30 mg/kg i.p.), quercetin (30 mg/kg i.p.), and flavon (20 mg/kg i.p.) showed marked inhibition of CNV formation. Flavon was particularly potent and almost completely inhibited the CNV formation.
• DN N-nitropyrazoles
• Ischemia of choroidal blood flow is closely related to the induction/triggering of AMD. Therefore, agents that are able to increase choroidal blood flow will be able to prevent choroidal ischemia and the triggering of AMD.
• choroidal ischemia can cause RPE cell degeneration, lipofusion accumulation, lyposomal activity changes and extracellular matrix formation.
• Bruch's membrane shows abnormality, thickening, and decreases in permeability that leads to the breakdown of the Bruch's membrane and the growth of CNV into the subfoveal areas.
• agents that can increase choroidal blood flow should be able to prevent/treat AMD from continuing to develop, if they are administered at the early stage of AMD.
• AMD rat model that develop CNV by breakdown of Brack's membrane by laser beam.
• Treatment of these AMD animal model with 1) hypotensive agents such as hydralazine, guanabenz, and D-timolol; 2) flavonoids including apigenin, naringenin, quercetin, and flavon; and 3) N-nitropyrazole derivatives such as DN-6, DN-7, DN- 13 at various dose levels showed potent inhibition of CNV formation which is the main etiology of AMD formation.
• agents as IL-I blockers are antagonists of IL-I induced uveitis.
• Intravitreal injection of IL-I induced ocular inflammation causes breakdown of the blood-aqueous barrier.
• fluorescein may cross the broken blood-aqueous barrier to enter the eye and to reach peak inflammation 12 hr after IL-I injection.
• IL-I is the most potent cytokine to induce inflammation which can be blocked effectively by prednisolone at 20 mg/kg t.i.d. ( Figure 13).
• 9 compounds showed potent blocking effects on IL-I induced uveitis.
• IL-2 blockers delay trabeculectomy failure caused by Inflammation.
• Trabeculectomy is used frequently for the treatment of narrow/closed angle glaucoma. However, it causes inflammation and failure of aqueous humor drainage after a short period of time after surgery.
• the synthetic IL-I blockers such as CK- 17, CK-IOlA and CK- 103 A prolonged the appearance of trabeculectomy failure through inhibition of inflammation caused by IL-I released from surgery ( Figure 14). They were all more effective than prednisolone to delay the trabeculectomy failure ( Figure 14). Thus, these agents could be used to prevent breakdown of Bruch's membrane and the development of CNV and AMD.
• IL-I blockers inhibition of systemic inflammation induced by carrageenin.
• Carrageenin is a potent inflammatory agent to cause pain and swelling on the joints.
• IL-I blockers such as CK- 17 was very effective in inhibiting carrageenin induced inflammation (Figure 15).
• CK-17 was about 10 times as potent as aspirin which is a standard agent used widely as anti-inflammatory, analgesic, and anti-arthritis drug (Table 15).
• IL-I blockers are therapeutically safe.
• LD 5O of both CK-17 was extremely high, at least 20g/kg orally, which is equivalent to l,400g/70kg for man. Since the ED 50 of these compounds was approximately 10mg/kg, the therapeutic index (LD 5 o/ED 50 ) would be higher than 2,000 (20,000 mg/kg ⁇ lOmg/kg).
• IL-I blockers provide negligible eye irritation.
• IL-I blocker suppress of CNV formation in rat eyes.
• Bruch's membrane was broken by laser beam, massive CNV was formed with marked fluorescein leakage in the fluorescein angiography as a control.
• the animals were treated by prednisolone at 3 mg/kg i.p. the CNV formation was markedly inhibited five out of eight CNV formations.
• CK-17 at 30 mg/kg i.p. showed even better results than prednisolone at 3 mg/kg i.p. by inhibiting at least six out of eight CNV spots (Fig 5).
• the results of CK-112 at 10 mg/kg i.p. were about the same as prednisolone at 3 mg/kg i.p. (Figs 4 and 6).
• the results were even better (Fig 7) and were about the same as that of CK-17 at 30 mg/kg i.p. (Fig 5).
• the effect of CK-113 at 30 mg/kg i.p. was similar to that of CK-112 at 10 mg/kg i.p. (Figs 7 and 8).
• prednisolone showed inhibition of CNV formation as expected.
• the toxicity of prednisolone and other steroidal anti-inflammatory agents provides concern for use in the clinics for the treatment of AMD.
• 3 mg/kg i.p. of prednisolone was the minimal dose required to produce inhibition of CNV formation.
• some animals lost appetite and body weight. Higher doses even resulted in the death of animals.
• CK compounds were quite non-toxic.
• CK-17 at 20 g/kg given orally did not cause any toxic response for at least 7 days observed whereas the effective dose to inhibit CNV formation was as low as 30 mg/kg i.p. Therefore, CK compounds can be used effectively and safely for the treatment of AMD through CNV formation inhibition.
• Synthetic compounds including CK-17, CKlOlA, CKl 03A, CK 112, CK
• ketamine 35 mg/kg ketamine and 5 mg/kg xylazine intramuscularly.
• Half of the initial dose was given hourly to maintain anesthesia.
• An ocular hypertensive model was created by raising the intraocular pressure of the left eye to 40 mmHg which reduced the ocular blood flow to approximately 1/3 of the normal values.
• the left ventricle was cannulated through the right carotid artery for the injection of microspheres, and the femoral artery was cannulated for blood sampling.
• One percent drug solution (50 ⁇ l) or vehicle (50 ⁇ l) was instilled topically to the left eye, and the ocular blood flow of the ocular hypertensive rabbits was measured with colored microspheres at 0, 30, 60, and 120 min thereafter.
• the Tissue/Blood Digest Reagent I was added to the microfuge tubes with the tissue samples, sealed, and heated at 95 0 C for 15 min. The tubes were vortexed for 30 sec, reheated and revortexed until all tissue samples were dissolved. The Tissue/Blood Digest Reagent II was added while the tissue samples were still hot, then the tubes were capped, vortexed, and centrifuged for 30 min. The protocol, thereafter, was the same as that used to process the blood sample, and the microspheres were counted.
• Qm is the blood flow of a tissue in terms of ⁇ L/min/mg
• Cm is the microsphere count per mg of tissue
• Qr is the flow rate of blood sample in terms of ⁇ L/min
• Cr is the total microsphere count in the referenced blood sample.
• Electroretino grams were determined to provide assessment of the retinal function prior to and following ischemic insult. ERGs were recorded by means of Ag/ AgCl electrodes placed in contact with the cornea. One stainless steel needle was inserted subcutaneously between the two eyes as a reference electrode, and another needle was inserted subcutaneously to the neck as a ground electrode. A photostimulator (Grass PS22 Flash) was used to produce flashes of light five inches from the eye, and the ERG potentials were recorded with a polygraph system. The ERG machine was purchased from LKC Technologies, Inc. (Gaithersburg, MD). A single (10 msec duration), white light stimuli was used to elicit ERG a- and b-waves. Peak b-wave amplitudes were measured from the trough of a-wave to the peak of b-wave.
• Example 5 Measurement of CNV Formation in Rat Eyes after Induction of Choroidal Neovascularization.
• Brown-Norway rats weighing 200 ⁇ 250g, were anesthetized with ketamine 35 mg/kg and xylazine 5 mg/kg. Pupils were dilated with a topical application of 1% tropicamide (Bausch & Lomb; Miami, FL) and 2.5% Neo-Synephrine (Sanofi- Synthelabo Inc.; NY). CNV was experimentally induced with a double frequency Nd:YAG laser (Laserex LP3532; Ellex Medical PTY. LTD., Australia) to disrupt Bruch's membrane. The laser wavelength was 532 nm, and spot size was 100 ⁇ m. Power delivered ranged from 130 to 150 mW, applied for 0.1 sec.
• Each laser lesion was evaluated as follows: Leaking (++): increase in size of hyperfluorescence over time; Non-leaking (+): only staining without increase in size of hyperfluorescence; Non-evaluation (-): fluorescein angiography could not evaluate the lesion due to masking by the overlying hemorrhage.
• Fluorescein Angiography Fluorescein Angiography was performed in anesthetized animals with dilated pupils using a Digital Fundus Camera (TRC-50 EX: Topcon, Japan) and standard fluorescein filter 0.3 ml of 10% fluorescein (Sigma- Aldrich Inc.; St. Louis, MO) was injected intravenously via hypoglossal vein. After injection, the camera alternated between both eyes taking images for 10 minutes. Fluorescein angiography was performed in all rats at 2 and 4 weeks following simultaneous laser induction of CNV and drug-vehicle injection.
• ketamine 35 mg/kg ketamine and 5 mg/kg xylazine intramuscularly.
• Ten ⁇ l of 1.0 ng of IL-l ⁇ were injected intravitreously with 30-gauge needle, and the rats were allowed to recover from the anesthesia.
• CK-compounds at doses of 3 mg/kg or 10 mg/kg, were injected intraperitoneally (i.p) at time 0, 4, and 10 hours after the IL-l ⁇ injection. The inflammation was measured 12 hours after IL-l ⁇ injection.
• the rats were anesthetized again as described previously, and FD-70 solution (1.4 ml/kg) was injected intravenously through the hypoglossal vein.
• Example 8 Trabeculectomy induced inflammation
• a glaucoma filtration operation with partial thickness scleral flap was completed using an operating microscope and a strict aseptic technique.
• a limbus based conjunctival flap was created.
• a partial thickness minifiap was formed in the sclera.
• the flap dimensions were three millimeters at the limbus, two millimeters on the sides and at the base.
• At the surgical limbus a 2.5 millimeter sclerostomy was performed using a razor blade chip.
• a Kelly Descement punch (Storz, St. Louis, MO) was then used to complete the sclerostomy.
• a peripheral iridectomy was then performed.
• the iris was reposited with a balanced salt solution flush and gentle corneal massage.
• the scleral flap was then sutured closed with a single 10-0 micorsurgical nylon suture and fixed with an overlying square knot.
• the conjunctiva and the tenons incision were closed with a running 10-0 suture.
• a filtration bleb could be noted. The same procedure was done on the contralateral eye.
• the rabbits Prior to surgery, the rabbits were randomly assigned to one of seven groups 1) vehicle control subtenons injection (STI), 2) prednisolone eye drops, 3) no drug 4) methylprednisolone STI, 5) CK- 17 STI, 6) CK-IOlA STI, and 7) CK- 102 STI.
• the animals in the eye drops group received two drops in each eye three times per day.
• the eye drops 50 ⁇ l treatment began the day before surgery and continued until failure of the fistula.
• the control for the eye drops group was "no drug" because the formulation of the eye drops is patented and therefore, a vehicle control could not be prepared.
• the rabbit was anesthetized with 1 mg/kg acepromazine IM. Inflammation scores were calculated and recorded. At the conclusion of the experiment the animals were euthanized with an overdose (100 mg/kg) of pentobarbital sodium.
• LD50 determination For each dose, 20 mice of either sex, weighing 18-20 g were used to determined the LD 50 according to the method of Litchfield & Wilcoxon, J. Pharmacol. Exp. Ther. 96:99-113 (1949). Animals were housed in an animal room at 25 0 C and 70% relative humidity. The light cycle was set for 12 h light and 12 h darkness. CK- 17 was grounded with Tween 80 and then suspended in 1% CMC (carboxymethyl cellulose). The suspension was administered ig at 20 g/kg and the animals were observed for 7 d.
• CMC carboxymethyl cellulose
• Draize test Draize et al., J. Pharmacol. Exp. Ther. 82:377-90 (1944), was followed for the determination of eye irritation. Before the Draize test, it was already known that CK- 17 did not produce skin irritation in guinea pigs. So, Draize test was used to show the safety rather than the toxicity of drugs in the rabbit eyes in this experiment.
• Six New Zealand albino rabbits of either sex, weighing 2-2.5 kg were used in each group. Animals were housed individually in cages at 25 0 C and 70% relative humidity. The light cycle was maintained at 12 h light and 12 h dark for 7 d after the instillation of CK-17 or vehicle as controls.
• CK-17 (0.1%) was suspended in 6% dimethylsulfoxide (DMSO), 6% PEG

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