CYAN EXHIBIT 1021
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`lllllllllllllllll||l||IllllIllllllllllllllllllllllllIllllllllllllllllllllll
`U8005310764A
`
`United States Patent
`
`119]
`
`[11] Patent Number:
`
`5,310,764
`
`Baranowitz et al.
`
`[45] Date of Patent:
`
`May 10, 1994
`
`[54] TREATMENT OF AGE RELATED MACULAR
`DEGENERATION WITH BETA-CAROTENE
`
`[76]
`
`Inventors; Steven Baranowitz, 85 Tices La. -
`Apt. 39, East Brunswick, NJ. 08816;
`Andrew Brookner, 25 Spenser Dr.,
`Short Hills, NJ. 07078
`
`[21] Appl. No.: 880,709
`
`[22] Filed:
`
`May 8, 1992
`
`Int. 01.5 .............................................. A67K 31/07
`[51]
`[52] us. C1. ..................................... 514/725; 514/912
`[58] Field of Search ................................ 514/725, 912
`
`[56]
`
`References Cited
`PUBLICATIONS
`
`Health Periodicals Abstract of Western Journal of Med-
`icine, vol. 155 Issue No. 4, Oct. 1991.
`Kennekens et a1. Federal Research in Progesss. (The
`Research started on 1984).
`Steven A. Baranowitz, “Regeneration, Neural Crest
`Derivatives and Retinoids: A New Synthesis,” J. Theor.
`Biol, 140: 231—242, 1989.
`Garry J. Handelman et al., “Carotenoids in the Human
`Macula and Whole Retina,” Investigative Ophthalmol-
`ogy, 29:850-855, 1988.
`Richard W. Young, “Solar Radiation and Age—related
`Macular Degeneration," Survey of Ophthalmology,
`32:252—269, Jan.—-Feb., 1988.
`Richard W. Young, “Pathophysiology of Age—related
`Macular Degeneration,” Survey of Ophthalmology,
`31:291—306, 1987.
`Susan B. Bressler et al. “Relationship of Drusen and
`Abnormalities of the Retinal Pigment Epithelium to the
`Prognosis of Newvascular Macular Degeneration,”
`Arch Ophthalmol, 108:1442—1447, Oct, 1990.
`Neil M. Bressler et al., “Age—related Macular Degener-
`ation,” Survey of Ophthalomology, 32:375—413, May—-
`Jun, 1988.
`Howard Schatz et al., “Atrophic Macular Degeneration
`Rate of Spread of Geographic Atrophy and Visual
`Loss,” Ophthalmology, 96:1541—1551, 1989.
`J. P. Sarks et al., “Evolution of Geographic Atrophy of
`the Retinal Pigment Epithelium,” Eye, 2:552—577, 1988.
`D. Pauleikhoff et al., “Drusen as Risk Factors in
`
`Age-Related Macular Disease,” American Journal of
`Ophthmalogy, 109:38—43, Jan., 1990.
`W. T. Ham Jr. et al., “Basic Mechanisms Underlying
`the Production of Photochemical Lesions in Mamma-
`lian Retina,” Current Eye Research, 3:165-174, 1984.
`M. L. Katz et al., “Fluorescent Pigment Accumulation
`in Retinal Pigment Epithelium of Antioxidant—Defi—
`cient Rats,” Investigative Ophthalmology, 17: 1049—1058,
`1978.
`Martin L. Katz et al., “Relationship Between Dietary
`Retinol and Lipofuscin in the Retinal Pigment Epithe-
`lium,” Mechanisms of Ageing
`and Development,
`35:291-305, 1986.
`Martin L. Katz et al., “Development of Lipofuscin—-
`Like Fluorescence in the Retinal Pigment Epithelium in
`Response to Protease Inhibitor Treatment,” Mecha-
`nisms ofAgeing and Development, 49:23—40, 1989.
`C. Kathleen Dorey et al., “Cell Loss in the Aging Re-
`tina,” Investigative Ophthalmology, 30: 1691—1699, 1989.
`Glenn L. Wing et'al., “Topography and Age Relation-
`ship of Lipofuscin Concentration in the Retinal Pigment
`Epithelium,” Investigative OphthalmoIogy, 17, 601—607,
`1977.
`Sheila K. West at al., “Exposure to Sunlight and Other
`Risk Factors for Age-Related Macular Degeneration,”
`Arch Ophthalmol, 107:875—879, Jun., 1989.
`Mike Boulton et al., “The Formation of Autofluores-
`
`(List continued on next page.)
`
`Primary Examiner—Zohreh A. Fay
`Attorney, Agent, or Firm—Darby & Darby
`
`[57]
`
`ABSTRACI
`
`According to the present invention, there are provided
`methods for treating age related macular degeneration
`in a mammal; for preventing impairment of the vision or
`for improving impaired vision of a mammal whose eye
`has drusen; for preventing formation or growth of dru-
`sen in the eye of a mammal; and for reducing the num-
`ber or the size of drusen or for fading drusen without
`resultant areas .of retinal atrophy, without resultant
`impairment of vision, or without a combination of the
`foregoing in the eye of a mammal. Beta-carotene in
`appropriate amounts is administered to the mammal.
`
`19 Claims, 1 Drawing Sheet
`
`

`

`5,310,764
`
`Page 2
`
`OTHER PUBLICATIONS
`
`cent Granules in Cultured Human RPE,” Investigative
`Ophthalmology, 30:82—89, 1989.
`Mike Boulton et al., “Age—Related Changes in the Mor-
`phology, Absorption and Fluorescence of Melano»
`somes and Lipofuscin Granules of the Retinal Pigment
`Epithelium,” Visiain Research, 30:1291-1303, 1990.
`John D. Gottsch et al., “Hematogenous Photosensitiza-
`tion," Investigative Ophthalmology, 31:1674—1683, Sep.,
`1990.
`David A. Newsome et al., “Oral Zinc in Macular De-
`generation,” Arch Ophthalmol. 106:192—198, Feb., 1988.
`Sohrab Mobarhan et al., “Effects of B—Carotene Reple-
`tion on B—Carotene Absorption, Lipid Peroxidation,
`and Neutrophil Superoxide Formation in Young Men,"
`Nutrition & Cancer, 14:195—206, 1990.
`Shirley H. Sarks et al., “Age-related Macular Degener-
`ation: Atrophic Form,” Retina, Chapter 64, 2:149-173.
`
`1989.
`Peter A. Campochiaro et al., “Retinoic Acid Promotes
`Density-Dependent Growth Arrest in Human Retinal
`Pigment Epithelial Cells,” Investigative Ophthmology,
`32:65—72, 1991.
`R. J. Stephens et 211., “Vitamin E Distribution in Ocular
`Tissues Following Long—Term Dietary Depletion and
`Supplementation as Determined by Microdissection
`and Gas Chromatography-Mass Spectrometry,” Exp.
`Eye Research, 47:237-245, 1988.
`Craig E. Eldred, “Vitamins A and E in RPE Lipofuscin
`Formation and Implications For Age—Related Macular
`Degeneration,” Inherited and Environmentally Induced
`Retinal Degenerations, pp. 113—129, 1989.
`John J. Weiter, “Macular Degeneration”, Arch. Oph-
`thalmol, 106:183—198, Feb., 1988.
`Theo L. van der Schaft, et al., “Is Basal Laminar De-
`posit Unique for Age-Related Macular Degeneration?”
`Arch. Ophthalmol, 109:420—425, Mar., 1991.
`
`

`

`US. Patent
`
`May 10, 1994
`
`5,310,764
`
`I
`
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`1
`
`5,310,764
`
`TREATMENT OF AGE RELATED MACULAR
`DEGENERATION WITH BETA-CAROTENE
`
`FIELD OF THE INVENTION
`
`The invention relates to a method for the treatment of
`age related macular degeneration (ARMD) in the eyes
`of mammals. Beta-carotene is administered, preferably
`systemically, in a therapeutically effective amount.
`The administration of beta-carotene has also been
`found to prevent the growth or the formation of drusen,
`to reduce the number or the size of drusen, or to cause
`drusen to fade without resultant retinal atrophy or im-
`pairment of vision.
`BACKGROUND OF THE INVENTION
`
`Age related macular degeneration is a common de-
`generative disease of the retina and is the leading cause
`of blindness in the elderly. The disease is associated
`with chronological age, as ten percent of the individuals
`between the ages of sixty-five and seventy-five in the
`United States have lost some vision because of the dis-
`ease. Thirty percent of people over the age of seventy-
`five have lost some vision due to the disease. Young,
`“Pathophysiology of Age-related Macular Degenera-
`tion”, Survey of Ophthalmology, Vol. 31, No. 5, Mar-
`ch—April 1987.
`The basic anatomy of the eye is illustrated in FIG. 1.
`The sclera (1) forms the external tissue of the eyeball.
`The choroid (3) is the vascular layer beneath the sclera.
`The retina (5) lines the choroid (3) and is the nervous
`membrane upon the surface of which the images of
`external objects are received and then are transmitted
`through the optic nerve (11). Precisely in the center of
`the posterior part of the retina, corresponding to the
`axis of the eye, and at a point in which the sense of
`vision is perfect in a normal eye,
`is a yellowish area
`called the macula (7) which has a central depression,
`called the fovea (9). FIG. 2 illustrates that beneath the
`sensory retina is a single layer of pigmented epithelial
`cells called the retinal pigment epithelium (RPE) (1).
`Between the RPE and the choriocapiliaries is a mem-
`brane known as Bruch’s membrane (7).
`ARMD is believed to be caused by the deterioration
`and death of the retinal pigment epithelium. The cause
`of the degeneration is unknown, but it has been specu-
`lated that ARMD may be an advanced stage of the
`normal aging process. Young, Survey of Ophthalmology,
`Vol. 31, No. 5, March—April 1987. The variability in the
`age of onset of the disease is likely due to the variability
`in biological aging.
`The earliest and most obvious clinical sign of ARMD
`is the presence of drusen. Sarks et al. “Age-related Mac—
`ular Degeneration: Atrophic Form”, Retina, Vol. 2.,
`The C. V. Mosby Company, 1989. Drusen are extracel-
`lular masses of heterogeneous composition containing
`materials excreted from aging RPE cells and remnants
`of dead cells. Young, Survey of Ophthalmology, Vol. 31,
`No. 5, March—April 1987. They are situated between
`the basal membrane of the RPE and Bruch’s membrane.
`
`Young, Survey of Ophthalmology, Vol. 31, No. 5, Mar—
`ch—April 1987. Clinically, drusen are seen as localized
`yellowish deposits or excrescences lying deep to the
`retina. Bressler et al. “Age-related Macular Degenera—
`tion”, Survey of Ophthalmology, Vol. 32, No. 6, May—-
`June 1988.
`i.e. hard drusen, are seen in
`Small discrete drusen,
`eighty-three percent of normal adult eyes. Hard drusen
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`represent a localized disorder of only a few RPE cells.
`The RPE cells overlying the drusen are often thinned
`or pigmented. Bressler et al., Survey of Ophthalmology,
`Vol. 32, No. 6, May-June 1988.
`Larger areas of RPE dysfunction having ill defined,
`nondiscrete boundaries are termed soft drusen. Soft
`drusen are associated with more serious forms of
`ARMD in which there is significant loss of central
`vision. Soft drusen often merge into one another and
`become confluent.
`The interface between the choroid and the retina, the
`development of drusen, and the changes induced by
`drusen are illustrated in FIG. 2. On the far left, the
`retinal pigment epithelium (RPE) cells (1) contain only
`a few residual bodies (3), and these are largely confined
`to the base of the cells. Melanin granules (5) are present
`near the apical surface. Bruch’s membrane (7) is thin
`and uncontaminated. The visual cells (9) (of which only
`the inner and outer segments are shown) are regularly
`aligned and densely packed. This is the typical appear-
`ance in young eyes. In the adjacent region, early senes-
`cent changes are shown: the number of residual bodies
`(3) has increased throughout the RPE (1) cytoplasm,
`and Bruch’s membrane (7) has thickened. To the right,
`a druse (11) has been formed. On the surface of the
`druse, the attenuated RPE cells are engorged with re-
`sidual bodies, melanin has diminished in amount, some
`
`'of the visual cells have disappeared, and the remainder
`are physically distorted. Surviving rods and cones be-
`come shorter and broader as adjacent cells disappear.
`Patients can still have excellent visual acuity in the
`early stages of ARMD. Bressler et al., Survey of Oph-
`thalmology, Vol. 32, No. 6, May-June 1988.
`Loss of central vision can be attributed to several
`different occurrences, all of which relate to the drusen.
`Vision loss can occur when RPE and photoreceptor
`cells over the drusen degenerate and debris accumu-
`lates. Although the drusen fade and ultimately disap-
`pear, areas of atrophy remain. This fading is believed to
`be due to the activity of macrophages and adjacent
`RPE cells. This form of ARMD is termed geographic
`atrophy. Sarks et al., “Evolution of Geographic Atro-
`phy of the Retinal Pigment Epithelium", Eye. Vol. 2,
`552—577, 1988; see also Schatz eta1., “Atrophic Macular
`Degeneration”, Ophthalmology, 96, October 1989.
`Soft drusen can also cause vision loss by initiating
`breaks in Bruch’s membrane which allow the egress of
`fibrovascular tissue from the choriocapillaries. The
`fibrous tissue can lead to serous or hemorrhagic detach~
`merits of the sensory retina with accompanying severe
`loss of central vision.‘
`_
`Finally, drusen may become so abundant as to in-
`volve the fovea, interrupting the function of the sensory
`retina and resulting in vision loss.
`Research on the effects of phototoxicity in human
`and primate retinas has demonstrated some relationship
`between acute photic damage to the retina and the
`changes symptomatic of ARMD. Young, “Solar Radia-
`tion and Age-related Macular Degeneration”, Survey of
`Ophthalmology, Vol. 32, No. 4, January—February 1988.
`However, if ARMD were caused by chronic phototox-
`icity, one would expect an association between life~long
`light exposure and the prevalence of ARMD. Recent
`epidemiological studies indicate that there is no correla-
`tion between ARMD and the cumulative exposure of
`UV light. West et al., “Exposure to Sunlight and Other
`
`

`

`5,310,764
`
`4
`
`3
`Risk Factors for Age-related Macular Degeneration",
`Arch. Ophthalmol, Vol. 107, June 1989.
`Furthermore, various studies have been proposed or
`performed to determine the ediology of ARMD. Han-
`dleman et al., “Carotenoids in the Human Macula and
`Whole Retina”, Investigative Ophthalmology and Visual
`Science, Vol. 29, No. 6, 850—855, June 1988, found that
`the major carotenoids in the retina were lutea and zea-
`xanthin. No beta-carotene was found in the retina. Han-
`
`dleman et a]. proposed to prevent ARMD through the
`use of retinal carotenoids to confer antioxidant protec-
`tion. Handleman et a1. classified carotenoids as protec-
`tive agents against highly reactive singlet oxygen and
`proposed that singlet oxygen-induced liquid perOxida-
`tion was a mediator of light damage in the retina. Carot-
`enoid deficient monkeys were reported to show pig-
`ment changes in the fundus.
`Ham et al., “Basic Mechanisms Underlying the Pro-
`duction of Photochemical Lesions in the Mammalian
`
`Retina”, Current Eye Research, Vol.3, No, 1, 165~l74,
`1984, disclose that both vitamin E and beta-carotene are
`naturally occurring singlet oxygen quenchers and that
`the toxic combination of light and oxygen'leads to the
`generation of free radicals, a possible cause of phototox-
`icity.
`Vitamin E was suggested to be a likely vitamin A
`autoxidation inhibitor by Kat: et al., “Relationship be—
`tween Dietary Retinol and Lipofuscin in the Retinal
`Pigment Epithelium", Mechanisms of Aging and Devel-
`opment, Vol. 35, 291—305, 1986. See also Katz et a1.
`“Development of Lipofuscin-like Fluorescence in the
`Retinal Pigment Epithelium in Response to Protease
`Inhibitor Treatment”, Mechanisms of Aging and Devel-
`opment, Vol. 49, 23—40, 1989; Stephens et al., “Vitamin
`E Distribution in Occular Tissues Following Long-
`term Dietary Depletion and Supplementation as Deter-
`mined by Microdissection and Gas Chromatography-
`Mass Spectrometry", Experimental Eye Research, Vol.
`47, 237—245, 1988.
`Retinoids have been demonstrated to modulate the
`
`growth and differentiation of several types of cells by
`Campochiaro et al., “Retinoic Acid Promotes Density—
`Dependent Growth Arrest in Human Retinal Pigment
`Epithelial Cells", Investigative Ophthalmology and Visual
`Science, Vol. 32, No. 1, January 1991.
`‘
`Gottsch et al., “Hematogenous Photosensitization",
`Investigative Ophthalmology and Visual Science. Vol. 31,
`No. 9, September 1990, hypothesize that tissue damage
`due to photosensitization which in turn is due to free
`radical generation, may be prevented either by inducing
`protective enzymes using scavengers of free radicals
`and singlet oxygen such as vitamin E or by filtering the
`appropriate excitatory wavelengths. See also Boulton et
`al., “The Formulation of Autofluorescent Granules in
`Cultured Human RPE",
`Investigative Ophthalmology
`and Visual Science. Vol. 30, No. 1, January 1989. While
`Gottsch et al. suggest that beta-carotene and vitamin E
`are singlet oxygen quenchers, they strongly suggest that
`treatment of established disease is not aided by these
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`agents and that prophylaxis by vitamin E is not always
`effective.
`
`Katz et a1. “Flourescent Pigment Accumulation in
`Retinal Pigment Epithelium of Antioxidant-Deficient
`Rats“, Investigative Ophthalmoloy Visual, 1049-1058,
`1978, disclose that lipofuscin pigment in rats may be
`attributable to a diet that produces physiological antiox-
`idant deficiency. Young, Survey of Ophthalmology, Vol.
`32, No. 4, January-February 1988, discloses that beta-
`carotene can diminish photodynamic change in the
`retina. However, treatment of established ARMD is not
`disclosed, and no relationship between the presence or
`the growth of drusen and photodynamic damage is
`suggested.
`Because the normal retina has a high concentration of
`zinc, supplemental zinc was investigated in the treat—
`ment of ARMD by Newsome et a1. “Oral Zinc in Macu-
`lar Degeneration", Arch. Ophthalmology, Vol. 106, Feb-
`ruary 1988. No correlation of ARMD with initial serum
`levels of zinc was observed, and progression of the
`disease was seen in both the treatment and the non-
`
`treatment groups. Furthermore, zinc ingestion can be
`accompanied by serious side effects.
`It has now been discovered that the administration of
`
`appropriate amounts of beta-carotene can successfully
`treat ARMD. Beta~carotene had also proven useful in
`the inhibition and resolution of drusen, particularly
`without typical vision impairment or detrimental ana-
`tomical and physiological changes in the eye.
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 is a diagram of the anatomy of the eye.
`FIG. 2 is a diagram of the development of drusen.
`SUMMARY OF THE INVENTION
`
`According to the present invention, there is provided
`a method for treating age related macular degeneration
`in a mammal comprising administering to the mammal,
`a therapeutically effective amount of beta-carotene.
`The invention also contemplates a method for pre-
`venting impairment of the vision or for improving im-
`paired vision of a mammal whose eye has drusen com—
`prising administering to the mammal a therapeutically
`effective amount of beta-carotene.
`
`In a further embodiment, a method for preventing
`formation or growth of drusen in the eye of a mammal
`is provided. This method comprises administering to
`the mammal a drusen inhibiting effective amount of
`beta-carotene.
`
`Furthermore, a method for reducing the number or
`the size of drusen or for fading drusen without resultant
`areas of retinal atrophy, without resultant impairment
`of vision, or without a combination of the foregoing in
`the eye of a mammal is provided. Beta-carotene in a
`drusen reducing amount is administered to the mammal.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`Carotinoids are terpenes that are widely distributed in
`the plant and animal kingdoms. Beta-carotene is a com-
`mon carotinoid having the chemical structure:
`
`

`

`5,310,764
`
`
`
`Beta-carotene, in mammals, readily undergoes oxida-
`tive cleavage at the central double bond to give two
`equivalents of the aldehyde retinol. Biochemical reduc-
`tion of the aldehyde carbon yields vitamin A.
`Age related macular degeneration is a disease pre-
`dominantly of humans. The most disturbing symptoms
`of ARMD include a slow or sudden loss of central
`vision or vision distortion in one eye. However, ARMD
`is diagnosed by the visualization of drusen in the eye
`coupled with this vision loss.
`The diagnosis of ARMD is typically made by fundus-
`copy which reveals a pigmentary or hemorrhagic dis-
`turbance due to drusen in the macular region of the
`involved eye. The contralateral eye almost always
`shows some pigmentary disturbance and the presence of
`drusen in the macula. Fluorescein angiography can also
`be utilized in the diagnosis of ARMD. This procedure
`visualizes the neovascular membranes beneath the re—
`tina.
`
`Although the mere presence of drusen is not defini-
`tive of ARMD, typically, the presence of drusen will
`lead to the disease. Therefore, it is advantageous to be
`able to treat the presence of drusen by reducing the size
`or the amount of drusen or by fading the drusen before
`and without clinical impairment of vision due to the
`disease.
`Typically, drusen will grow or fade leaving resultant
`areas of retinal atrophy. This retinal atrophy leads to
`vision loss. Drusen can cause vision loss through other
`mechanisms, however. Drusen can cause degeneration
`of the retinal pigment epithelial cells, photoreceptor
`cells, or a combination thereof. Visual impairment can
`also be due to one or more breaks in the Bruch’s mem-
`brane which permit the egress of fibrovascular tissues
`from choriocapillaries. Finally, the vision impairment
`can be due to the formation or growth of drusen itself
`which becomes sufficient to cover a significant portion
`of the fovea.
`Applicants hypothesize, without being bound to any
`particular theory, that by increasing the availability of
`carotinoids, and particularly beta~carotene, to the reti-
`nal pigment epithelium, function can be normalized. In
`fact, it has been suspected for some time that carotinoids
`are present in the human eye as reflected by the term
`macula lutea, lutea meaning yellow.
`In all of the embodiments of the present invention,
`beta-carotene is preferably administered systemically.
`Systemic administration most preferably is by the oral
`route.
`
`The term “daily dosage" identifies the average
`amount of beta-carotene administered to a patient.
`However, the dosage need not be administered daily.
`The daily dosage is merely an average dosage that a
`patient receives when beta-carotene is administered
`over a period. The daily dosage can be administered in
`divided portions so that the total amount administered is
`the daily dosage. Typically, acceptable blood levels of
`beta-carotene and chemically detectable changes in
`blood levels will be achieved after administration of
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`beta-carotene in the prescribed amounts for several
`months, i.e. three to six months.
`Although the safe upper limit of the amount of beta-
`carotene that can be administered to a human has not
`yet been determined, it is believed that such an upper
`limit is at least 1000 mg/day.
`In the treatment of age related macular degeneration
`or in the prevention or improvement of impaired vision
`in an eye with drusen, beta-carotene is administered in a
`therapeutically effective amount. Therapeutically effec—
`tive amounts of beta-carotene are those amounts suffi-
`cient to stabilize the progression of the disease or to
`resolve the symptoms of ARMD. This amount will
`depend upon the age, weight, sex, sensitivity, and the
`like of the individual. In many mammals, the therapeuti-
`cally effective amount can be determined by experimen-
`tation well known in the art such as by establishing a
`matrix of dosages and frequencies and assigning a group
`of experimental subjects to each point in the matrix.
`Typically for a human being, that amount will be at
`least about 50 mg/day of beta-carotene. Most prefera-
`bly, that amount will range from about 60 mg/day to
`' about 350 mg/day. Particularly,
`the dosage will be
`about 240 ing/day.
`The amount of beta-carotene required to prevent
`formation or growth of drusen is a drusen inhibiting
`amount of beta-carotene. Again, this amount will de-
`pend upon the age, weight, sex, sensitivity, and the like
`of the individual. This amount can be determined exper-
`imentally as explained above. Preferably, drusen inhibit-
`ing amounts of beta-carotene will be at least about 50
`mg/day. Most preferably, that amount will range from
`about 60 mg/day to about 350 mg/day. Particularly,
`the dosage will be about 240 mg/day.
`The amount of beta-carotene required to reduce the
`number or the size of drusen or to fade drusen is a dru-
`sen reducing amount of beta-carotene. Again that
`amount may be determined experimentally as explained
`above. Typically for a human being, that amount will be
`at least about 50 mg/day. Most preferably, that amount
`ranges from about 60 mg/day to about 350 mg/day.
`Particularly, the dosage will be about 240 mg/day.
`Although beta-carotene is provided through normal
`diet, the amounts of beta-carotene useful in the present
`invention typically are not provided by normal diet.
`This is because the foods that supply beta—carotene in
`the normal diet contain various other substances. If
`sufficient amounts of these foods were consumed to
`provide the necessary amounts of beta-carotene, these
`other substances would have been consumed in toxic
`amounts. Therefore, beta-carotene is typically supplied
`in the methods of the present invention through supple-
`mentation. Commercially available forms of beta-caro-
`tene are available, for example, from Hoffman-LaRoche
`under the trademark SOLATENE TM or as “beta-caro-
`tene”.
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`last for
`Typically, a course of administration will
`about three months to several years and preferably to
`
`

`

`7
`about three years. If new or further impairment of vi-
`sion, deveIOpment or growth of drusen, or symptoms of
`the disease occur in a subject who has been treated
`according to the present invention, it may become nec-
`essary to repeat the administration, to adjust the dosage
`of beta-carotene, or to administer a maintenance effec-
`tive amount of beta-carotene. This maintenance effec-
`tive amount of betacarotene will be that amount which
`will prevent regression to pretreatment conditions. This
`amount may be the same as or less than the amount used
`during treatment.
`DESCRIPTION OF THE PREFERRED
`EMBODIMENTS
`
`The following examples illustrate the invention with-
`out limitation. Drusen are counted from funduscopy
`photographs and are counted as lighter areas proximate
`to the fovea.
`'
`
`EXAMPLE 1
`
`An 87 year old male was initially diagnosed as having
`bilateral cataracts and ARMD. The patient underwent
`cataract surgery on one eye about one year after the
`initial diagnosis and underwent cataract surgery on the
`other eye about one year after the first surgery.
`About one year and two months after the last surgery
`(Examination 1), funduscopy revealed a large number
`of drusen in each eye. One year and two months later,
`(Examination 2), visual acuity was measured as 20/20 in
`the right eye and 20/30 in the left eye. The patient was
`placed on a regimen of 60 mg/day of beta-carotene.
`About one month later (Examination 3), visual acuity
`was measured as 20/25 in the right eye and 20/30 in the
`left eye. The patient was placed on a regimen of 120
`mg/day of beta-carotene. About one month later (Ex-
`amination 4), visual acuity was measured at 20/30 in the
`right eye and 20/30 in the left eye. The patient was
`placed on'a regimen of 180 mg/day of beta-carotene.
`About one month later, (Examination 5), visual acuity
`was measured as 20/25 in the right eye and 20/30 in the
`left eye. The patient was placed on a regimen of 240
`mg/day of beta-carotene.
`Visual acuity was measured periodically over the
`next three months and ranged from 20/20 to 20/25 in
`the right eye and 20/25 to 20/30 in the left eye, while
`the patient was maintained on the 240 mg/day beta-
`carotene regimen. Funduscopy at the end of this period
`(Examination 6), revealed a 35.8 percent decrease in the
`number of drusen in one eye and a 68.7 percent decrease
`in the number of drusen in the other eye. The decrease
`in drusen was determined by comparing the number of
`drusen seen at Examination 1 and Examination 6. Many
`drusen also decreased in size during this period. Initial
`and final drusen counts are compared in Table 1.
`EXAMPLE 2
`
`An 84 year old female was initially diagnosed as hav-
`ing bilateral cataracts and ARMD. The patient under-
`went cataract surgery on the left eye two weeks after
`the diagnosis and underwent cataract surgery on the
`right eye approximately two and one half months after
`the first surgery. Branch vein occlusion was diagnosed
`in the left eye about one year and two months after the
`initial diagnosis, and central vein occlusion was diag-
`nosed in the left eye about four months subsequently.
`About three years after the initial diagnosis of ARMD
`(Examination 1), visual acuity was measured as 20/ 100
`in the right eye and count fingers vision in the left eye.
`
`5,310,764
`
`5
`
`IO
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`The patient was placed on a regimen of 60 mg/day of
`beta-carotene.
`About one month later (Examination 2), visual acuity
`was measured as 20/200 in the right eye and count
`fingers vision in the left eye. The patient was placed on
`a regimen of 120 mg/day of beta-carotene.
`About month later (Examination 3), visual acuity was
`measured as 20/70 in the right eye and count fingers
`vision in the left eye. Funduscopy revealed a concentra-
`tion of drusen in the foveal area of one eye. The patient
`was placed on a regimen of 180 mg/day of beta-caro-
`tene.
`
`About month later (Examination 4) visual acuity was
`measured as 20/70 in the right eye and count fingers
`vision in the left eye. The patient was placed on a regi-
`men of 24-0 mg/day of beta-carotene.
`Visual acuity was measured periodically over the
`next four months and ranged from 20/70 to 20/80 in the
`right eye and remained count fingers vision in the left
`eye, while the patient was maintained on a regimen of
`240 mg/day of beta-carotene. Later, visual acuity in the
`right eye was 20/80 and count fingers vision in the left
`eye.
`Funduscopy at the end of this period (Examination
`5), revealed a 90.9 percent decrease in drusen in the eye
`previously photographed, a sharp reduction in the fo-
`veal region. The decrease in drusen was determined by
`comparing the number of drusen seen at Examination 3
`and Examination 5. Initial and final drusen counts are
`compared in Table 1.
`EXAMPLE 3
`
`A 70 year old female was initially diagnosed as hav-
`ing bilateral cataracts and ARMD. The patient under-
`went cataract surgery on the left eye about ten months
`later. About one year after surgery (Examination 1),
`visual acuity was measured as 20/25 in the right eye and
`20/20 in the left eye. Funduscopy revealed the presence
`of drusen in the foveal region of one eye. The patient
`was placed on a regimen of 60 mg/day of beta-carotene.
`About one month later (Examination 2), visual acuity
`was measured as 20/30 in the right eye and 20/20 in the
`left eye. The patient was continued on the same regimen
`of beta-carotene.
`About one and one half months later (Examination 3),
`visual acuity was measured as 20/30 in the right eye and
`20/20 in the left eye. The patient was placed on a regi-
`men of 120 mg/day of beta-carotene.
`’
`About one month later (Examination 4), visual acuity
`was measured as 20/25 in the right eye and 20/20 in the
`left eye. Funduscopy revealed a 25 percent decrease in
`the number of drusen and a marked decrease in the
`amount of drusen in the foveal area of the eye previ-
`ously photographed. The decrease in drusen was deter-
`mined by comparing the number of drusen seen at Ex-
`amination l and Examination 4. The patient was placed
`on a regimen of 180 mg/day of beta-carotene. Initial
`and final drusen counts are compared in Table 1.
`One and one half months later, visual acuity in the left
`eye was measured as 20/30 and visual acuity in the right
`eye was measured as 20/20. The patient was placed on
`a regimen of 240 mg/day of beta—carotene.
`EXAMPLE 4
`
`An 86 year old male was initially diagnosed as having
`bilateral cataracts and ARMD. The patient underwent
`cataract surgery in the right eye, about five months
`after the initial diagnosis. Three years and three months
`
`

`

`9
`after the initial visit (Examination 1), the patient’s visual
`acuity was measured as 20/40 in the right eye and 20/40
`in the left eye. Funduscopy revealed the presence of
`drusen in the foveal area of one eye.
`About two months later (Examination 2), visual acu-
`ity was measured as 20/30 in the right eye and 20/30 in
`the left eye. The patient was placed on a regimen of 180
`mg/day of beta-carotene.
`About one month later (Examination 3), visual acuity
`was measured as 20/40 in the right eye and 20/30 in the
`left eye. Funduscopy revealed an increase in the amount
`of drusen in the foveal area of the eye previously photo-
`graphed. The patient was placed on a regimen of 240
`mg/day of beta-carotene.
`Over about the following four months visual acuity
`ranged from 20/30 to 20/40 in the right eye and 20/30
`to 20/40 in the left eye, while the patient was main-
`tained on a dosage of 240 mg/day of beta-carotene.
`About one month after this period (Examination 4),
`visual acuity was measured as 20/40 in the right eye and
`20/40 in the left eye. Funduscopy revealed a 40 percent
`decrease in the amount of drusen in the eye previously
`photographed. The decrease was determined by com-
`paring the number of drusen seen at Examination 1 and
`Examination 4. The patient was maintained on the regi~
`men of 240 mg/day of beta-carotene. Initial and final
`drusen counts are compared in Table 1.
`Examples 1—4 demonstrate the remarkable transfor-
`mation of and reduction in number and size of drusen as
`well as the successful treatment of ARMD due to beta-
`carotene administration in accordance with the present
`invention.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`1