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
  • A61K31/60—Salicylic acid; Derivatives thereof
  • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
  • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
• • 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
• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
  • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
• • 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
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
  • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/19—Cytokines; Lymphokines; Interferons
  • A61K38/191—Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/19—Cytokines; Lymphokines; Interferons
  • A61K38/20—Interleukins [IL]
  • A61K38/2006—IL-1
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N5/00—Radiation therapy
  • A61N5/06—Radiation therapy using light
  • A61N5/067—Radiation therapy using light using laser light
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
  • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting in contact-lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
  • A61F9/0008—Introducing ophthalmic products into the ocular cavity or retaining products therein

Definitions

• the sources of oxidative stress in the eye include a number of possibilities.
• the partial list of endogenous sources encompasses phagocytic cells, most notably, neutrophils, macrophages and eosinophils, which are potent generators of oxidants.
• biochemical reactions involving cycloxygenase, nitric oxide (NO) synthase and other enzymatic reactions can lead to oxidative stress.
• Enhanced mitochondrial metabolism of oxygen also produces superoxide anion (O 2 ') and other reactive species of oxygen.
• Exogenous sources of oxidative stress include cigarette smoking, various drugs and photooxidative reactions caused by irradiation to the eye as a consequence of sunlight or laser therapy.
• Oxidative stress occurs in the eye during both health and disease.
• the mitochondrial consumption of O 2 generates oxygen radicals which may not be completely detoxified by antioxidants and consequently, may produce oxidative stress.
• ARMD the leading cause of blindness in the elderly, a condition in which deposits of an oxidized lipid, lipofuscin, are manifest in the retina.
• Levels of hydrogen peroxide (H 2 O 2 ) are also increased in the vitreous of the eye and is believed to contribute to cataract, glaucoma and/or other ocular abnormalities.
• the eye is often subjected to reactions that generate inflammation activating immune and inflammatory cells and other cellular functions that produce oxidative stress.
• Oxidative stress is defined as an increase in the production of highly reactive species of oxygen and/or nitrogen ("free radicals") and/or a decrease in antioxidant defense systems.
• Antioxidant defense systems encompass enzymatic and non-enzymatic detoxifying mechanisms, binders of various cofactors, such as metals that facilitate oxidative reactions, and molecular alterations that make cellular lipids, membranes or DNA less susceptible to damage by oxidants.
• Nuclear factor- ⁇ B is a heterodimeric transcription factor complex that mediates multiple immune and inflammatory responses.
• the activated form of NFKB consists of two proteins, a p65 (aka rel A) subunit and a p50 subunit.
• Rel, rel BV, v-rel and p52 may also be a part of NFKB and different forms of activated NFKB may activate different sets of target genes.
• Activation of NFKB in the cytoplasm is associated with a series of events that facilitate the transport of NFKB to the nucleus when it has its effects on centrally controlled genetic processes (see Figure 1).
• Interleukin-2 receptor ( ⁇ chain) Interleukin-2 receptor ( ⁇ chain)
• NFKB neurotrophic factor
• one complex scheme could involve elaboration of neutrophils from the bone marrow, production of chemotaxins, recruitment and activation of neutrophils and the release of enzymes and oxidants from neutrophils. The latter is facilitated by COX2 (prostaglandins, thromboxanes), NO synthase and other molecules which increase blood flow and blood vessel permeability.
• COX2 prostaglandins, thromboxanes
• NO synthase other molecules which increase blood flow and blood vessel permeability.
• the effectiveness of interventions may be assessed by observing changes that occur in these marks or predictors. Using any single factor is not as effective a using a battery of factors since increases or decreases in individual factors may not reflect the concerted response needed to cause ARDS.
• a still further object is to provide a method that augments other ways or improving vision including, without limitation, mechanical low vision aids, laser therapy, acupuncture, plasmaphoresis, and retinal transplants.
• An additional objective is to provide a new method for using NFKB or NFKB related responses to predict or reflect the development of ocular oxidative stress, to assess individuals in whom oxidative stress is more likely to occur, to quantitate the extent of oxidative stress and/or to monitor the effect of one or more interventions.
• the present invention is based on the discovery that NFKB modulation can decrease oxidation stress and that activation of NFKB by oxidative stress can be decreased by methods that reduce oxidative stress.
• the present invention provides a method for maintaining eye health as well as treating eye disorders in which oxidative stress is a cause and/or a contributing factor.
• N acetylcysteine
• Figure 2 is a figure that depicts a mechanism whereby NFKB dependent processes could contribute to ocular oxidative stress.
• Figure 3 indicates the yin-yang responses controlled by NFKB.
• NFKB neuropeptide-binding protein
• ESA electrophoretic mobility shift analysis
• Inhibitor effectiveness strategies are examined by applying various concentrations of the agent before and following analysis of NFKB activation.
• inhibitors are also identified by testing agents that inhibit the l ⁇ b subunits or other parts of the mechanism by which NFKB modulators both in up- or down-regulating ways.
• agents that inhibit the l ⁇ b subunits or other parts of the mechanism by which NFKB modulators both in up- or down-regulating ways are tested to control NFKB and NF ⁇ B-dependent response using genetic manipulations of the promotor and/or other systems which regulate NFKB by that mechanism.
• various cell types are tested to determine NFKB activation which is believed to occur differently in different cell types e.g. the lung is different than the eye and consequently inhibitors are identified that are effective in the eye.
• NFKB activities in mammalian ocular and other tissues are examined from various subjects that have been subjected to various conditions and/or various interventions. Using the same approaches as described above, organs and/or cells are isolated and cellular extractions are obtained to identify the levels of NFKB. Once the appropriate circumstances are identified, the agents that are postulated to be causing NFKB alterations in vitro are retested in simplified cellular systems in vitro. This approach identifies agents and approaches that are better for ocular tissues since NFKB activation and inactivation and its consequences vary in different cells.
• a further aspect of the present invention is the use of fragments of IL-1, TNF or other molecules that activate NFKB to produce resistance to oxidative stress.
• Selected fragments of IL- 1 activate certain immune functions that are also activated by native IL- 1.
• a novel fragment of IL-1 (or other molecule) is selected that activates NFKB and confers resistance to oxidative stress without inducing all of the other actions that follow administration of native IL- 1 or these other similar molecules.
• the approach regarding stimulation relates in concept to the use of RAS activators, oxidants, stress reaction, UV, viruses, growth factors and toxicological agents either in their native state, or in a specifically modified state, alone and/or in combination.
• An isolated nucleic acid molecule of the present invention can be obtained from its natural source either as an entire (i.e., complete) gene or a portion thereof capable of forming a stable hybrid with that gene.
• An isolated nucleic acid molecule can also be produced using recombinant DNA technology (e.g., polymerase chain reaction (PCR) amplification, cloning) or chemical synthesis.
• Isolated nucleic acid molecules include natural nucleic acid molecules and homologues thereof, including, but not limited to, natural allelic variants and modified nucleic acid molecules in which nucleotides have been inserted, deleted, substituted, and/or inverted in such a manner that such modifications provide the desired effect.
• An isolated nucleic acid molecule of the present invention can include degeneracies.
• the present invention includes a recombinant vector, which includes at least one isolated nucleic acid molecule of the present invention, inserted into any vector capable of delivering the nucleic acid molecule to a desired tissue.
• a vector can contain nucleic acid sequences that are not naturally found adjacent to the isolated nucleic acid molecules to be inserted into the vector.
• the vector can be either RNA or DNA and typically is a plasmid.
• One type of recombinant vector referred to herein as a recombinant molecule and described in more detail below, can be used in the expression of nucleic acid molecules.
• the maximal size of a nucleic acid molecule in that the nucleic acid molecule can include a portion of a gene, an entire gene, or multiple genes, or portions thereof.
• the minimal size of a protein homologue of the present invention is from about 4 to about 6 amino acids in length, with preferred sizes depending on whether a full-length, multivalent (i.e., fusion protein having more than one domain each of which has a function), or functional portions of such proteins are desired.

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• Proteomics, Peptides & Aminoacids (AREA)
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• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Radiology & Medical Imaging (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 2000
  • 2000-08-09 CA CA002350715A patent/CA2350715A1/en not_active Abandoned
  • 2000-08-09 EP EP00961334A patent/EP1119352A4/de not_active Withdrawn
  • 2000-08-09 WO PCT/US2000/021784 patent/WO2001024794A1/en not_active Ceased
  • 2000-08-09 AU AU73302/00A patent/AU7330200A/en not_active Abandoned

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