WO1997048388A1 - Procede de retardement et d'attenuation d'affections oculaires et du systeme nerveux central - Google Patents

Procede de retardement et d'attenuation d'affections oculaires et du systeme nerveux central Download PDF

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WO1997048388A1
WO1997048388A1 PCT/US1997/010496 US9710496W WO9748388A1 WO 1997048388 A1 WO1997048388 A1 WO 1997048388A1 US 9710496 W US9710496 W US 9710496W WO 9748388 A1 WO9748388 A1 WO 9748388A1
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lutein
retinal
injury
damage
eye
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PCT/US1997/010496
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English (en)
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Mark O. M. Tso
Tim-Tak Lam
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The Board Of Trustees Of The University Of Illinois
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Publication of WO1997048388A1 publication Critical patent/WO1997048388A1/fr

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    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A

Definitions

  • the present invention relates to a method of retarding and ameliorating central nervous system and eye diseases. More particularly, the present invention is directed to methods of treating central nervous system and eye insult resulting from disease or injury, such as age-related macular degeneration, photic injury, photoreceptor cell, or ganglion cell damage, traumatic injury, ischemic insult-related diseases and inflammatory diseases.
  • the method comprises administering a therapeutically effective amount of lutein to an individual, either orally, topically, or parenterally, to ameliorate damage caused by the disease or injury or to retard the progress of a degenerative disease.
  • Eye diseases and injuries of the central nervous system presently are not treatable. These diseases and injuries are untreatable because, un ⁇ like many peripheral organs that can be removed in whole or in part, or transplanted, the central ner ⁇ vous system has very limited regeneration capability and cannot be totally excised without death.
  • the eye is an extension of the brain, and, therefore, a part of the central nervous system. Accordingly, in the case of an eye injury or disease, i.e., a reti ⁇ nal injury or disease, the diseases are often with- out treatment and the eye cannot be transplanted.
  • Eye diseases and injuries that presently are un- treatable include retinal photic injury, retinal ischemia-induced eye injury, age-related macular degeneration, and other eye diseases and injuries that are induced by free radical species.
  • Singlet oxygen and free radical species can be gen ⁇ erated by a combination of light and oxygen, or during reperfusion after an ischemic insult.
  • the eye is subjected to continuous light exposure because the primary purpose of the eye is light perception. Therefore, some untreatable diseases and injuries to the eye result from the continuous exposure of the eye to light, coupled with the highly oxygenated environment in the eye.
  • the process of light perception is initi- ated in the photoreceptor cells.
  • the photoreceptor cells are a constituent of the outer neuronal layer of the retina, which is a component of the central nervous system.
  • the photoreceptor cells are well sheltered in the center of the eye, and are protect- ed structurally by the sclera, nourished by the highly vascularized uvea and safeguarded by the blood-retinal barrier of the retinal pigment epithe ⁇ lium.
  • the primary function of the photoreceptor cells is to convert light into a physio-chemical signal (transduction) and to transmit this signal to the other neurons (transmission) .
  • transduction a physio-chemical signal
  • transmission a signal to the other neurons
  • the metabolic activities of these neurons are changed dramatical- ly.
  • the photoreceptor cells are secure ⁇ ly protected in the interior of the eye, these cells are readily accessible to light because their prima ⁇ ry function is light detection. Excessive light energy reaching the retina can cause damage to these neurons, either directly or indirectly, by over ⁇ whelming the metabolic systems of these cells.
  • Singlet oxygen and free radical species also can be generated by enzymatic processes independent from light exposure.
  • the free radical species and singlet oxygen are reactive entities that can oxi ⁇ dize polyunsaturated fatty acids.
  • the retina con ⁇ tains the highest concentration of polyunsaturated fatty acids of any tissue in the human body, and peroxidation of the polyunsaturated fatty acids in cell membranes of the retina by hydroxyl radicals
  • the ocular media including the cornea, aqueous, lens, and vitreous, filter most of the light in the ultraviolet region.
  • the photoreceptor cells also possess other forms of protection from photic injury, for example, the presence of antioxidant compounds to counteract the free radical species generated by light.
  • antioxidants which quench and/or scavenge singlet oxygen, hydrogen peroxide, superoxide and radical species, help minimize injury to the photo ⁇ receptor cells.
  • the human eye has an excessive number of photoreceptor cells such that only destruction of a significant number of photore- ceptor cells adversely affects visual function.
  • age-related photoreceptor degeneration Even though several protective mechanisms are present in the eye, a leading cause of blindness in the United States is age-related photoreceptor degeneration.
  • photoreceptor degenera- tion as seen in age-related macular degeneration, is causally related to excessive exposure to blue light.
  • the causes of age-related macular degenera ⁇ tion which is characterized by a loss of photore ⁇ ceptor neurons resulting in decreased vision, are being investigated.
  • photic injury is a cause of age-related macular degeneration because of the cumulative effect of repeated mild photic insult which leads to a gradual loss of photoreceptor cells.
  • Age-related macular' degeneration is an irreversible blinding disease of the retina. Unlike cataract wherein vision can be restored by replacing the diseased lens, age-related macular degeneration cannot be treated by replacing the diseased retina because the retina is a component of the central nervous system. Therefore, because no treatment for this disease exists once the photoreceptors are destroyed, prevention is the only way to confront age-related macular degeneration.
  • pre ⁇ vention of age-related macular degeneration resides in limiting or preventing light and oxygen-induced (i.e., free radical-induced) damage to the retina because tne retina is the only organ that is contin- uously exposed to high levels of light in a highly oxygenated environment.
  • eye injury and disease can result from singlet oxygen and free radical species generated during reperfusion after an ischemic insult.
  • Ischemic insult to retinal ganglion cells and to neurons of the inner layers of retina causes loss of vision.
  • Loss of vision accom ⁇ panies diabetic retinopathy, retinal arterial occlu ⁇ sion, retinal venous occlusion and glaucoma, each of which ischemically insults the eye, i.e., deprives the eye of oxygen and nutrition.
  • the damage to the retinal ganglion cells has been attributed to ischemia, and subsequent reperfusion during which free radicals are generat ⁇ ed.
  • the reoxygenation of tissue after an ischemic insult results in a relatively high concentration of oxygen flowing through the effected tissue, which contributes to free radical formation.
  • Ischemic insult and reperfusion accompa ⁇ nied by free radical generation also is a major contributor to central nervous system damage, such as damage caused by a stroke.
  • Ascorbate was investigated as an agent to treat retinal photic injury. Ascorbate is a reducing agent which is present in the retina in a high concentration. Studies indicated that ascorbate in the retina can act as an antioxidant and is oxidized by free radical species generated during excessive light exposure.
  • Ascorbate mitigates retinal photic injury be ⁇ cause of its antioxidant properties, which are at- tributed to its redox properties.
  • Ascorbate is a scavenger of superoxide radicals and hydroxy radi ⁇ cals and also quenches singlet oxygen and reduces hydrogen peroxide, all of which are formed in reti ⁇ nal photic injury. This hypothesis accounts for the presence of high levels of naturally occurring ascorbate in a normal retina.
  • antioxidants which inhibit free radical formation, or which quench singlet oxygen and scavenge for free radical species can decrease lipid peroxidation and ameliorate photic injury and ischemic/reperfusion injury in the central nervous system, and particularly in the retina.
  • Antioxi ⁇ dants originally were investigated because they are known constituents of human tissue. However, anti- oxidants that are not naturally occurring in human tissue also were tested.
  • antioxidants such as 2,6-di-tert- butylphenol, 7-oryzanol, ⁇ -tocopherol, mannitol, reduced glutathione, and various carotenoids have been studied for an ability to quench singlet oxygen and scavenge free radical species.
  • antioxidants are effective quenchers and scavengers for singlet oxygen and free radicals.
  • the carotenoid ⁇ as a class of compounds, are very effective singlet oxygen quenchers and free radical scavengers.
  • individual carotenoids differ in their ability to quench singlet oxygen and scavenge for free radical species.
  • the carotenoids are naturally occurring compounds that have antioxidant properties.
  • the carotenoids are common compounds manufactured by plants or animals, and contribute greatly to the coloring of plants and animals.
  • a number of ani- mals, including mammals, are unable to synthesize carotenoids de novo and accordingly rely upon diet to provide carotenoid requirements. Mammals also have a limited ability to modify carotenoids.
  • a mammal can convert /3-carotene to vitamin A, but most other carotenoids are deposited in mammalian tissue in unchanged form.
  • carote ⁇ noids With respect to humans, about ten carote ⁇ noids are found in human serum.
  • the major carote ⁇ noids in human serum are ⁇ -carotene, ⁇ -carotene, cryptoxanthin, lycopene, and lutein. Small amounts of zeaxanthin, phytofluene, and phytoene are found in human organs.
  • zeaxanthin and lu ⁇ tein are found in the human retina.
  • Zeaxanthin is the predominant carotenoid in the macula and is concentrated in the cone cells in the center of the retina, i.e., the macula. Lutein is located in the peripheral retina in the rod cells.
  • the eye preferentially assimilates zeaxanthin over lu- tein in the macula and also selectively concentrates zeaxanthin, which is a more effective singlet oxygen scavenger than lutein, in the center of the eye. It has been theorized that zeaxanthin and lutein are concentrated in the retina because of their ability to quench singlet oxygen and scavenge free radicals, and thereby limit or prevent photic damage to the retina. However, the natural amounts of zeaxanthin and lutein concentration in the retina are insuffi- cient to protect the eye from major insults, or to treat the eye.
  • Beta-carotene and lycopene the two most abundant carotenoids in human serum, either have not been detected or have been detected only in minor amounts in the retina.
  • Beta- carotene is relatively inaccessible to the retina because /3-carotene is unable to cross the blood- retinal brain barrier of the retinal pigment epithe ⁇ lium effectively. As will be explained in detail hereinafter, small amounts of /3-carotene have been found to cross the blood-retinal brain barrier.
  • canthaxanthin can cross the blood-retinal brain barrier and reach the retina.
  • Canthaxanthin like all carotenoids, is a pigment and can discolor the skin.
  • Canthaxanthin provides a skin color that approximates a suntan, and accordingly has been used by humans to generate an artificial suntan.
  • Howev ⁇ er an undesirable side effect in individuals that ingested canthaxanthin at high doses for an extended time was the formation of crystalline canthaxanthin deposits in the inner layers of the retina.
  • the blood-retinal brain barrier of the retinal pigment epithelium permits only particular carote ⁇ noids to enter the retina.
  • the carotenoids other than zeaxanthin and lutein that do enter the retina cause adverse effects, such as the formation of crystalline deposits by canthaxanthin, which may take several years to dissolve. Canthaxanthin in the retina also caused a decreased adaptation to the dark.
  • carotenoids are strong antioxidants
  • investigators have failed to find particular carotenoids among the 600 natu- rally occurring carotenoids that effectively quench singlet oxygen and scavenge for free radical spe ⁇ cies, that are capable of crossing the blood-retinal brain barrier, that do not exhibit the adverse af ⁇ fects of canthaxanthin after crossing the blood- retinal brain barrier, and that ameliorate central nervous system or eye disease or injury and/or re ⁇ tard the progression of a degenerative disease of the central nervous system or eye.
  • the present invention is directed to meth ⁇ ods of treating individuals suffering from central nervous system injury or disease. More particular- ly, the present invention is directed to methods of treating individuals suffering from an eye injury or disease, and particularly retinal injury or disease, and to methods of retarding a degenerative disease of the eye.
  • the method comprises administering a ther ⁇ apeutically effective amount of lutein to an indi ⁇ vidual to retard a degenerative disease, or to ame ⁇ liorate, or treat, damage to the central nervous system caused by a disease or an injury.
  • the method comprises administering a therapeu ⁇ tically effective amount of lutein to an individual to improve the vision of an individual suffering from eye damage caused by disease or injury.
  • the lutein can be administered parenterally, orally, or topically. Specifically, oral feeding ⁇ of lutein re ⁇ ult in an increase of carotenoids in the rat retina.
  • the method is used to treat free radical- induced eye damage, light-induced eye damage, photo- receptor cell damage, ganglion cell damage, damage to neurons of inner retinal layers, and age-related macular degeneration.
  • the present method also ame- liorate ⁇ neuronal damage to the retina, wherein the neuronal damage is a result of photic injury, or ischemic, inflammatory, glaucomatous, or degenera ⁇ tive insult.
  • One aspect of the present invention is to administer about 1 to about 500 milligrams (mg) of lutein, and preferably about 5 to about 200 mg, per kilogram (kg) of body weight per dose, to retard a degenerative disease of the central nervous system or the eye, or to ameliorate damage resulting from an injury or a disease of the central nervous system or the eye.
  • mg milligrams
  • kg kilogram
  • Another aspect of the present invention is to provide a method of treating an inflammatory disea ⁇ e of the eye by administering a therapeutical ⁇ ly effective amount of lutein to an individual.
  • Another aspect of the present invention is to treat diseases and injuries to the central ner ⁇ vous system by administering a therapeutically ef- fective amount of lutein to an individual.
  • the method is used to treat diseases and injuries ef ⁇ fecting the brain, eye and spinal cord, such as injury caused by spinal cord trauma or by a stroke or neurodegenerative diseases.
  • FIG. 1 is a bar graph showing the thick- ne ⁇ of the inner retinal layer (IRT) in micrometer ⁇ ( ⁇ m) comparing the retinas of control animals to the retina ⁇ of animal ⁇ after ischemic insult treated with different doses of lutein.
  • IRT inner retinal layer
  • Neuronal degeneration of the central nervous system or the eye can result from photic injury, ischemic or intraocular pres ⁇ sure-related insult, e.g., an occlusion or a stroke, or from a trauma, e.g., trauma to the spinal cord.
  • the damage also can result from injury to the photo ⁇ receptor cells, to the ganglion cells in the retina of the eye or to neurons in the inner retinal layers of the eye, or from age-related macular degenera- tion.
  • antioxidants have been horrin gated, such as for example, ascorbic acid, ⁇ -tocoph- erol and /3-carotene.
  • Some investigator ⁇ have fo ⁇ cused on the carotenoids, e.g., 0-carotene, becau ⁇ e over 600 carotenoid ⁇ are known, are naturally occur ⁇ ring (and, therefore, are abundant) , and are strong antioxidant ⁇ .
  • Al ⁇ o with re ⁇ pect to the eye ⁇ , two carotenoids, zeaxanthin and lutein, which are strong antioxidants, are found in the photoreceptor cells of the retina.
  • human plasma includes about ten carotenoids, only these two carotenoids are able to effectively cross the blood-retinal brain barrier and concentrate in the macula of the eye.
  • zeaxanthin and lutein can cross the blood-retinal brain barrier, the naturally occurring amounts of these carotenoids in the eye have not retarded or ameliorated eye, or central nervous sy ⁇ tem, disease or injury.
  • Beta-carotene the most abundant human plasma carotenoid, has a very limited ability to cross the blood-retinal brain barrier. The ability of a carotenoid to pass the blood-retinal brain barrier is important because carotenoids are not synthesized by the human body. The only source of carotenoids for humans is dietary intake.
  • carotenoids that are not normal constituent ⁇ of human plasma, but have an ability to cros ⁇ the blood-retinal brain barrier, have demon ⁇ trated adverse affects on the retina.
  • Canthaxanthin which is intentionally ingested to provide an artificial suntan has accumulated in the retina in the form of crystal ⁇ and has temporarily affected eye adaptation to the dark.
  • /3-carotene has a limited ability to cross the blood- retinal brain barrier.
  • carotenoids are known as strong antioxidant ⁇ and are present in abundant supply, the carotenoids have not been used for the treatment of central nervous sy ⁇ tem damage, or eye damage, caused by disease or injury.
  • the carotenoids investigated to date either could not effectively cross the blood-retinal barrier (i.e., ⁇ -carotene) or adversely affected the eye (i.e., canthaxanthin) .
  • Carotenoids that can cross the blood-retinal barrier e.g., lutein
  • lutein which is a naturally occurring compound and is a strong antioxidant, is used in a method to ameliorate and retard, or pre- vent, cell damage in an individual suffering from a degenerative, inflammatory, or traumatic disease or injury to the central nervous sy ⁇ tem, particularly to the eye, and more particularly to the retina.
  • the administration of a thera ⁇ Implantically effective amount of lutein to an individ ⁇ ual prevents, retard ⁇ and/or treat ⁇ free radical- induced damage re ⁇ ulting from di ⁇ ea ⁇ e or injury, ⁇ uch as a trauma.
  • damage to a retina can result from either photic injury, neurodegener- ative disease or an ischemic insult followed by reperfusion.
  • lutein decrea ⁇ es the los ⁇ of photoreceptor cell ⁇ .
  • lutein ameliorates the los ⁇ of ganglion cell ⁇ and the inner layer ⁇ of the retinal neuronal network.
  • the carotenoid ⁇ are terpenoid compound ⁇ which are widely di ⁇ tributed in nature, and which ⁇ electively ab ⁇ orb light.
  • About 600 carotenoids have been isolated and identified from various vegetable and animal sources. Animals can ⁇ not synthe ⁇ ize carotenoid ⁇ de novo, but rely upon plant sources. Therefore, animals rely on dietary intake for carotenoids. Animals however can modify carotenoids. The ability to modify carotenoid ⁇ i ⁇ very limited in human ⁇ .
  • Carotenoid ⁇ are cla ⁇ ified into two major group ⁇ : (1) the carotene ⁇ , which are hydrocarbon ⁇ , and (2) the xanthophyll ⁇ , which include oxygen in addition to carbon and hydrogen.
  • the xanthophyll ⁇ can be con ⁇ idered oxidation product ⁇ of the caro ⁇ tene ⁇ , and are prepared by the insertion of oxygen into carotenes and sub ⁇ equent rearrangement ⁇ .
  • the mo ⁇ t common carotenoid is the carotene, /3-carotene. The following illustrate ⁇ the chemical structure of various carotenoid ⁇ :
  • /S-carotene is the most abundant carotenoid in human plasma, but typically is not found in the retina. Small amounts of j8-carotene are found in the retina if 0-carotene is administered in high doses intraperitoneally or orally. These results indicate that /S-carotene has great difficulty in crossing the blood-retinal brain barrier.
  • zeaxanthin and lutein both of which are very similar in structure to /3-carotene, are concentrated in the retina even though zeaxanthin and lutein are present in only minor amount ⁇ in human plasma.
  • zeaxanthin and lutein do not treat or pre- vent eye damage or disease in amounts naturally present in the retina.
  • Canthaxanthin which is a strong antioxidant and which has a structure similar to zeaxanthin and lutein, ha ⁇ the ability to cro ⁇ the blood-retinal brain barrier.
  • cantha- xanthin accumulates in the retina to form crystals.
  • the carotenoids differ greatly with respect to an ability to quench singlet oxygen and scavenge for free radicals.
  • DiMascio publication reported the following ability of carotenoids to quench singlet oxygen: astaxanthin>canthaxathin>/3-carotene>zeaxanthin>lutein> > ⁇ -tocopherol.
  • the above-identified Miki publication reported the following ability of carotenoid ⁇ to scavenge for free radical species: astaxanthin > zeaxanthin > canthaxanthin > lutein > 0-carotene > ⁇ -tocopherol. Therefore, minor ⁇ tructural difference ⁇ affect the ability of a carotenoid to act as an antioxidant in general, and more particularly to act a ⁇ a ⁇ inglet oxygen quencher or a free radical ⁇ cavenger.
  • Lutein also termed /3-e-carotene-3,3'- diol, is an abundant, naturally occurring compound. Lutein is the major pigment of algae and higher plants, like fruits and vegetables, and is one of the most widely distributed xanthophylls in the ani ⁇ mal kingdom. The prime source of lutein is algae and the petals of yellow flowers. Lutein is avail- able from Kemin Food ⁇ , L.C., De ⁇ Moines, Iowa a ⁇
  • the retinal pigment epithelium protects the retina by providing a blood- retinal brain barrier.
  • the barrier excludes plasma constituents that are potentially harmful to the retina.
  • the blood-reti ⁇ nal brain barrier only permits lutein and zeaxanthin to enter the retina, and excludes other carotenoid ⁇ pre ⁇ ent in human ⁇ erum, including /3-carotene which is the mo ⁇ t abundant carotenoid in human ⁇ erum.
  • lutein i ⁇ not pre ⁇ ent in the retina in a ⁇ ufficient amount to treat or prevent eye damage, especially damage resulting from major insults, such as eye damage resulting from ischemia or overexpo- ⁇ ure to light.
  • a lutein in 1.0 mL of 1.0% aqueou ⁇ TWEEN-80 (to provide two rat ⁇ with a do ⁇ e of 1, 10, or 30 mg/kg/- injection) .
  • Two other albino rat ⁇ were injected with 1.0 mL ⁇ olution of 1.0% aqueou ⁇ TWEEN-80 a ⁇ a control.
  • the injections were administered at 12 hour intervals starting at 24 hours before retinal ischemic insult. Two additional rat ⁇ were used as untreated controls.
  • the ten rats were anesthetized with an intraperitoneal injection of chloral hydrate (400 mg/kg) . Then, bilateral ischemic insult was induced by elevating intraocular pres ⁇ ure (IOP) through an infusion cannula to the anterior chamber. The IOP was maintained at 110 mm (millimeter) Hg for 60 minutes. Then, the cannulas were removed, and reperfusion of ocular vessel ⁇ was established by fundu ⁇ examination. All ten rats were euthanized 7 days after reperfu ⁇ ion with an overdoe ⁇ of pentobar- bital. Both eyes of each rat were enucleated and fixed in a 0.1M phosphate buffer and 1% glutaralde- hyde and 4% formaldehyde solution (by weight) .
  • IOP intraocular pres ⁇ ure
  • the posterior segment of each fixed enucle ⁇ ated eye was divided into the superior (S) , temporal (T) , inferior (I) and nasal (N) quadrants.
  • S superior
  • T temporal
  • I inferior
  • N nasal
  • Morphologic and morphometric evaluations were performed on 1 ⁇ m sections stained with methylene blue. The degree of ischemic insult was evaluated by measuring the average thickness
  • IRT internal limiting membrane
  • OPL outer plexiform layer
  • ONL outer nuclear layer
  • the IRT for the control rats was about 50 ⁇ m.
  • the normal IRT for a rat that was not subjected to retinal ischemic insult was 120 ⁇ m.
  • the lutein- treated rat ⁇ having an IRT about 32 ⁇ m thicker than the untreated rat ⁇ , demonstrated that lutein provid ⁇ ed statistically significant protection to the gan ⁇ glion cells and other neuronal elements of the inner retina from ischemic insult. It was noted that increasing the amount of lutein per injection did not further increase the IRT, but good results were obtained using a lutein dose of 1 to 30 mg/kg/- injection.
  • the in vivo test results illustrated in FIG. 1 show the ability of lutein to protect neurons and neuronal elements of the retina from ischemic and intraocular pres ⁇ ure-related injury to neurons of the inner layers of retina.
  • the test ⁇ have ⁇ hown that lutein can protect or rescue neuron ⁇ and other cell type ⁇ , and that lutein is an effective thera ⁇ Terminator agent to ameliorate photoreceptor degenera ⁇ tion and ischemic damage to neurons of the retina.
  • lutein has a protective effect on the central nervous sy ⁇ tem in general, especially damage to the brain and ⁇ pinal cord caused by free radi ⁇ cals.
  • the above tests show that the administra ⁇ tion of a therapeutically effective amount of lutein to an individual prevents, retards and/or amelio ⁇ rates damage to the central nervous system, and especially to the eye, resulting from disease or injury.
  • the lutein is administered to the individu ⁇ al in doses of about 1 to about 500 mg (milligram) lutein per kilogram (kg) of body weight.
  • the lutein dose is about 5 to about 200 mg lutein, and more preferably about 10 to about 200 mg lutein, per kg of body weight.
  • the lutein dose i ⁇ about 25 to about 150 mg lutein/kg of body weight.
  • the optimal lutein dose can be determined by a person skilled in the art after considering factors such as the disease or injury to be treated, the severity of the central nervous system damage, and the route of administration (i.e., oral, topical or parenterally) .
  • the lutein doses can be adminis ⁇ tered daily or in accordance with a regimen deter ⁇ mined by a person skilled in the art, with the length of treatment depending upon the severity and nature of the injury to the central nervous system.
  • the lutein can be administered to an indi ⁇ vidual parenterally, orally, or topically.
  • the lutein When administered orally, can be, for example, in the form of a liquid preparation, a tablet or as a component of food.
  • the lutein When applied topically, the lutein can be, for example, in the form of an eye drop composition for direct application to the eyes.
  • the free radical- induced damage can be attributed to light-induced injury or to injury resulting from an ischemic in ⁇ sult and subsequent reperfusion or neurodegenerative di ⁇ eases.
  • the administration of lutein also helps prevent and retard photic injury in addition to treating photic injury.
  • the administration of lutein ameliorates photoreceptor cell damage that is light induced, and ameliorates ganglion cell damage that is induced by ischemic insult and subsequent reperfusion.
  • the administration of lutein also retards the progress of degenerative eye diseases and beneficiates the vision of individuals suffering from a degenerative eye disease, such as age-related macular degenera ⁇ tion.
  • the admini ⁇ tration of lutein al ⁇ o provide ⁇ a method of treating i ⁇ chemic retinal di ⁇ eases, such as diabetic retinopathy, cy ⁇ toid macular edema, central retinal arterial occlu ⁇ ion, central retinal venous occlusion and glaucoma.
  • lutein administration is useful in treating inflammatory diseases of the eye such as retinitis, uveitis, ulceris, keratitis and scleritis wherein free radi- cal ⁇ are produced in abundance.
  • i ⁇ chemic retinal diseases and inflammatory diseases of the eye are free radical related.
  • the anti- oxidant propertie ⁇ of lutein coupled with the abil ⁇ ity of lutein to cro ⁇ s the blood-retinal brain bar ⁇ rier, lack of toxicity of lutein, and the lack of adverse side effects associated with lutein make lutein a useful compound to treat or prevent such free radical-related diseases.
  • lutein is a highly effective anti ⁇ oxidant and ameliorates free radical-induced eye damage
  • the administration of lutein also provides a method of treating free radical-induced disease or injury to the central nervous system in general.
  • a therapeutically effective amount of lutein can be administered to stroke victim ⁇ to ameliorate the ischemic in ⁇ ult-related injury at ⁇ tributed to the ⁇ troke.
  • Lutein also can be adminis ⁇ tered to individuals suffering from a traumatic injury to the spinal cord which leads to free radi ⁇ cal-induced damage.
  • Investigators have long searched for ef ⁇ fective antioxidants that can ameliorate neuronal damage.
  • a suitable antioxidant must have the abili ⁇ ty to cross the blood-retinal brain barrier, and must have a low toxicity.
  • the antioxidant either could not effectively pas ⁇ the blood-retinal brain barrier (e.g. , /3-carotene) or are toxic or exhibited adver ⁇ e side effects (e.g., canthaxanthin).
  • Lutein i ⁇ a natural, nontoxic product, and to date has not been shown to be toxic or exhibit adver ⁇ e ⁇ ide effect ⁇ even after the administration of large dose ⁇ of lutein for prolonged time periods.
  • lutein ha ⁇ not demonstrated the di ⁇ advantageou ⁇ side effects of closely structurally related canthaxan- thin and 0-carotene with respect to forming cry ⁇ tal ⁇ in the retina or decrea ⁇ ing adaptation to the dark.

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Abstract

L'invention concerne un procédé pour retarder et atténuer les affections et lésions oculaires. Ledit procédé consiste à administrer de la lutéine en dose thérapeutiquement efficace pour la prévention, le retardement ou le traitement d'affections ou lésions oculaires et du système nerveux central, tels que la dégénérescence maculaire due à l'âge et d'autres maladies dégénératives du système nerveux central, les troubles photiques, les affections ischémiques et inflammatoires.
PCT/US1997/010496 1996-06-17 1997-06-16 Procede de retardement et d'attenuation d'affections oculaires et du systeme nerveux central WO1997048388A1 (fr)

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US66435096A 1996-06-17 1996-06-17
US08/664,350 1996-06-17

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NL1010351C2 (nl) * 1998-10-19 2001-01-08 Werklust & Beheer B V Esters van caroteno´den voor gebruik in de preventie en behandeling van oogaandoeningen.
WO2006002735A1 (fr) * 2004-06-29 2006-01-12 Dsm Ip Assets B.V. Amelioration de la qualite de l'image dans l'oeil
US8012513B2 (en) 2006-06-08 2011-09-06 The Procter & Gamble Company Method for promoting eye health
KR101233114B1 (ko) * 2010-07-07 2013-02-14 강원대학교산학협력단 녹차 아세톤 추출물을 함유하는 황반 변성 예방 및 치료용 조성물
US8703737B2 (en) 2010-12-31 2014-04-22 Abbott Laboratories Nutritional formulations including human milk oligosaccharides and antioxidants and uses thereof
US8802650B2 (en) 2010-12-31 2014-08-12 Abbott Laboratories Methods of using human milk oligosaccharides for improving airway respiratory health
US9283240B2 (en) 2010-12-31 2016-03-15 Abbott Laboratories Human milk oligosaccharides for modulating inflammation
US9539269B2 (en) 2010-12-31 2017-01-10 Abbott Laboratories Methods for decreasing the incidence of necrotizing enterocolitis in infants, toddlers, or children using human milk oligosaccharides
US9763970B2 (en) 2010-12-31 2017-09-19 Abbott Laboratories Nutritional compositions comprising human milk oligosaccharides and nucleotides and uses thereof for treating and/or preventing enteric viral infection
US9795623B2 (en) 2010-12-31 2017-10-24 Abbott Laboratories Methods for reducing the incidence of oxidative stress using human milk oligosaccharides, vitamin C and anti-inflammatory agents
US10639319B2 (en) 2011-08-29 2020-05-05 Abbott Laboratories Human milk oligosaccharides for preventing injury and/or promoting healing of the gastrointestinal tract
US11337990B2 (en) 2010-12-31 2022-05-24 Abbott Laboratories Human milk oligosaccharides to promote growth of beneficial bacteria

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Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL1010351C2 (nl) * 1998-10-19 2001-01-08 Werklust & Beheer B V Esters van caroteno´den voor gebruik in de preventie en behandeling van oogaandoeningen.
WO2006002735A1 (fr) * 2004-06-29 2006-01-12 Dsm Ip Assets B.V. Amelioration de la qualite de l'image dans l'oeil
US20140161913A1 (en) * 2006-06-08 2014-06-12 The Iams Company Method for Improving Eye Health
US8012513B2 (en) 2006-06-08 2011-09-06 The Procter & Gamble Company Method for promoting eye health
US8389028B2 (en) 2006-06-08 2013-03-05 The Iams Company Method for promoting eye health
US8691296B2 (en) 2006-06-08 2014-04-08 The Iams Company Method for improving eye health
KR101233114B1 (ko) * 2010-07-07 2013-02-14 강원대학교산학협력단 녹차 아세톤 추출물을 함유하는 황반 변성 예방 및 치료용 조성물
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