WO1991004717A1

WO1991004717A1 - Armd-related vision impairment treatment

Info

Publication number: WO1991004717A1
Application number: PCT/US1990/005538
Authority: WO
Inventors: John D. Gottsch
Original assignee: Gottsch John D
Priority date: 1989-09-28
Filing date: 1990-09-28
Publication date: 1991-04-18
Also published as: AU6604890A

Abstract

Method and optical devices (10) for the amelioration of the visual degeneration in an individual susceptible to impairment of vision from age-related macular degeneration (ARMD) which employs a lens (12) which filters the macular damaging superoxide and/or singlet oxygen generating protoporphyrin IX excitatory wavelengths from the light entering the eyes of the susceptible individual.

Description

ARMD-RELATED VISION IMPAIRMENT TREATMENT

Background of the Invention

This invention relates to methods and devices for the treatment of age-related macular degeneration (ARMD) . ARMD is one of the leading causes of severe visual loss in the United States. The prevalence of the disease in its mildest form, viz. , the presence of drusen with minimal pigmentation and retention of good vision, has been reported in about 25% of the general population. Leibowitz, H.M. , et al., Surv. Ophthalmol. 24 Suppl: 428-457, 1986) . Those who develop visual loss of 20/30 or greater due to drusen or serous or hemorrhagic de¬ tachment of the retina compromise 1.2% of the population less than 65 years of age and 19.7% of the population 75 years and older.

Several theories of the pathogenesis of ARMD have been proposed based on histopathological observations where sclerosis and alterations of the choriocapillaris were noted by several investigators. (Verhoeff, F.H., et al., Arch. Ophthalmol. 18: 561-585, 1937; Duke-Elder, S., "System of Ophthalmology," vol. 9, p. 610 (Klimpton, London) ; Kornzweig, A.L., Ann. Ophthalmol. 9: 753-764, 1977.) However, a correlation between ARMD and high blood pressure as a cause of arteriosclerotic changes or elevated LDL and cholesterol as a cause of athero¬ sclerotic changes in the choriocapillaris have not been documented.

Primary dysfunction of the RPE has been suggested by some investigators as a cause of ARMD, who argue that with senescence the RPE may no longer be competent to perform its many and varied functions and eventually degenerates. However, the early histopathologic changes in ARMD occur in the choriocapillaris and Bruch's mem- brane. It is not clear why dysfunctional RPE should first manifest itself through changes in Bruch's membrane and the choroid.

The role of light exposure has been investigated by many as causing retinal damage. However, all reported experiments on light toxicity were conducted at high light levels for short durations. As yet there have been no animal models of ARMD produced with low level ambient illumination. Acute photic injury with high intensity illumination causes damage to photoreceptors and the retinal pigment epithelium (RPE) .

Because some ultraviolet radiation (UV) penetrates the ocular media to the retina, the possibility that ARMD is related to chronic UV exposure has been investigated. (West, S.K. , et al., Arch. Ophthalmol. 107: 875-879, 1989.) Long-term exposure to ultraviolet radiation (UVB) has been found to be associated with the development of cortical cataracts. (Taylor, H.R., et al., N. Engl. J. Med. 319: 1429-1433, 1988.) However, in the same population no association between chronic exposure to UVA (320-340 nm) or UVB (340-400 n ) and ARMD was found. (West, S.K., et al., supra.)

The development of ARMD proceeds with certain histo¬ pathologic characteristics. Hyalinization of Bruch's membrane and the choriocapillaris are the earliest mani- festation of the disease. Gradual thickening initially occurs in the inner aspect of Bruch's membrane with an increase in PAS-positive material and collagen. The thickened area of Bruch's membrane is weakened which can lead to localized detachments forming focal excrescences termed drusen. The pattern of drusen formation corres¬ ponds to the circulation of the choriocapillaris, par¬ ticularly over collecting vessels lending support to a theory of a hematogenous etiology of the disease. Choroidal neovascularization is associated with diffuse drusen formation and disciform scarring.

The eye is the only anatomic location of the body where light by design passes through optically clear tissue to be focused on a delicate structure (the retina) juxtaposed to highly vascular tissue (the choriocapil¬ laris) . This is a unique anatomic location where focused light, oxygenated blood, and delicate tissues interact. Presumably, the photooxidants produced in the chorio¬ capillaris are at low levels. However, it appears that chronic exposure to these photogenerated compounds over a long life span results in significant damage in suscept¬ ible individuals. The large amounts of superoxide dis- mutase (SOD) in erythrocytes presumably would protect against superoxide photogeneration. However, if one or several protective systems are compromised, superoxide formation may not be quenched or could be accelerated and increased damage to the choriocapillaris and Bruch's membrane could occur. Compromised protective mechanisms could include (1) decreased amounts of RPE pigment allowing more light to pass through to the choriocapil¬ laris, as evidenced by the fact that ARMD has been dem¬ onstrated to occur more frequently in lightly pigmented eyes, and less frequently in darkly pigmented eyes; (2) a decrease in SOD activity as a result of a) decreased production of SOD with age, b) increase in inactive enzymes with age because of lack of metallic (zinc, copper, manganese) or other cofactors; and/or c) heredi- tary causes for decreased levels of protective enzymes.

It has been postulated that the erythrocytic photohemoly- sis which occurs in patients with protoporphyria may be related to membrane damage from the free radical superoxide. The data described herein conclusively demonstrate superoxide photogeneration that correlates with its excitation spectrum. No hydroxyl radical was detectable. The demonstration that singlet oxygen is photogenerated by protoporphyrin IX (PP IX) is significant in that there is no protective scavenging enzyme for this molecule. Membrane damage by singlet oxygen generation has been suspected previously by the detection of lipid peroxidation and cholesterol hydroperoxide in protoporphyric erythrocytic membranes. Although β-carotene (presently the treatment of choice for erythropoietic protoporphyria) and vitamin E are excellent quenching compounds for singlet oxygen, the data described herein demonstrate decreased photogeneration of this oxidant with increasing wavelengths. These data suggest that both superoxide and singlet oxygen photogeneration can be greatly reduced by filtering the shorter wavelengths, particularly violet to blue light. Lipid peroxides may induce the molecular injury that occurs to capillary and Bruch's membranes. Presumably the injury caused by free radical penetration of these membranes would necessitate a reparative pro¬ cess. This injury may be the disturbance of the interac- tion of the choriocapillaris, Bruch's membrane and pigment epithelium that Tso has inferred as a cause of drusen formation. (Tso MOM, Ophthalmol. 92: 628-635, 1985.) Thickening of Bruch's membrane is a consistent feature found beneath retinal pigment epithelial cells that have degenerated with the development of drusen. Specifically, PAS-positive material and collagen have been identified as aging changes in Bruch's mem¬ brane. In erythropoietic protoporphyria, a disease in which cutaneous plaques develop in light-exposed areas, collagen and amorphous PAS-positive material have been found in blood vessel basement membrane. The thickened basement membranes seen in both patients with erythro¬ poietic protoporphyria and age-related macular degeneration may represent the same response to injury. In the eye, the thickened Bruch's membrane and possibly damaged basal cellular organelles would impair the ex¬ change of nutrients and waste products to and from the retinal pigment epithelium. The retinal pigment epi¬ thelium could become progressively compromised, such that it could no longer adequately support the outer retina. Based on this mechanism, dysfunctional RPE could be expected to occur more frequently over the choriocapil¬ laris network. This hypothesis is supported by the reported observations in flat preparations of the choriocapillaris that drusen overlie the intercapillary septia blood vessels. The weakened and thickened Bruch's membrane could lead to focal detachments. Difficulty with processing shed rod outer segments could inspissate the cell, leading to the formation of drusen. The induced hypoxia of the outer retina, because of the compromised retinal pigment epithelium, could stimulate release of angiogenic factors leading to subretinal neovascular proliferation and disciform scarring.

The prevalence of macular degeneration increases after the age of 65 years and reaches 27% in both men and women aged 75 to 85. Leibowitz, H.M. et al., Surv. Ophthalmol. 1980:24 (Suppl. ):335-610. Numerous risk factors have been investigated, but the pathogenesis of ARMD has remained elusive. According to Tso, Mark D.M. , Ophthal. 1985:92(5) 628-634, even though the pathogenesis of age-related macular degeneration has not been determined, epidemiologic, clinical and laboratory evidences suggest that many etiologic factors are involved. "Blue rays" have been identified as the cause of macular degeneration by a distributor of sunglasses said to filter out "damaging U.V. and blue rays." The author states that hereditary influence, photic injury, nutritional deficiency, toxic insult, immunologic disorders, systemic cardiovascular or respiratory disturbances, and preexisting eye diseases have been implicated. These different etiologic factors may, according to Tso, inflict damage on the macula individually or synergistically, resulting Ln a common set of clinical manifestations, interpreted as age- related macular degeneration.

Tso cites Noel, W.K. , Vision Res. 1980; 20:1163-71, and Feeney, et al., Ophthalmol. 1976:15:789-92, for the proposition that light induces production of superoxide radicals that inflict lipid peroxidation of photoreceptor outer segment membranes. Tso hypothesizes that a rela¬ tive deficiency in ascorbate (a scavenger for superoxide radicals) may make the aged more susceptible to light damage and result in ARMD. The authors conducted ex¬ periments involving exposure of the macula of baboons to the light of an indirect ophthalmoscope for a half-hour, which suggested to Tso that ascorbate may be one of the important anti-oxidants in the neural retina with protective function against photic injury to the retina. Neither Tso, nor Feeney and Noel cited by him, sug¬ gest that photic-generated superoxide radicals were the cause of ARMD. Tso and the Noel and Feeney articles cited by Tso all concern photic injury with high inten- sity light demonstrating damage to the photoreceptors. This is not the damage that is noted in age-related macular degeneration. The damage in age-related macular degeneration occurs in the choriocapillaris and in Bruch's membrane early in the course of disease. I discuss in my article, beginning on page 5, last para¬ graph, why these experiments do not apply to the conditions that cause age-related macular degeneration. Corning Medical Optics (Corning, NY) markets CPF® Filter lenses which filter blue, as well as ultraviolet light, while transmitting the remaining portion of the visible light, to help improve visibility and reduce glare and haze in persons with impaired vision from developing cataracts, aphakia or pseudaphakia, post-laser surgery, macular degeneration, diabetic retinopa hy, glaucoma, corneal dystrophy, optic atrophy, albinism, retinitis pigmentosa, aniridia, and other conditions causing severe light sensitivity. U.S. Patent No. 4,390,676 discloses and claims U.V.- absorbing intraocular lenses for use by aphakics to compensate for the loss of ultraviolet-absorbing capacity resulting from the loss of the natural lens. Although the ultraviolet range of the spectrum ends at about 380 nm, the claimed lenses are described as absorbing in a measurable amount up to 450 nm. Although the amount absorbed between 380 and 450 nm is not disclosed, less than about 30% transmission at 400 nm is preferred and U.V. absorbers with cut-off (0% transmission) wavelengths of 390 nm are disclosed. The addition of an amount of a visible light absorber which absorbs light in the visible range, in order to limit transmission of a minor percentage (no more than about 30%) of the visible light through the lens and onto the retina, is preferred, with dyes with an orange color disclosed as seeming to give the best results. Such a lens is ineffective in ameliorating the progressive loss of vision due to ARMD (because it merely replaces the loss of wavelength absorption (about 340 to about 400 nm) which occurred as a result of the loss of the natural lens of an aphakic individual, which protection already necessarily is ineffectual in an individual suffering from ARMD.

This invention is based upon the discovery that ARMD occurs in susceptible individuals as a result of exposure to even low-intensity visible light in the protopor- phyrin IX excitatory spectrum (ca. 340-600 nm) and that only by protecting the eye at substantially all times from damaging amounts of all of those wavelengths can one prevent or ameliorate the progression of ARMD in susceptible individuals.

Although sunglasses are commercially available which filter blue as well as ultraviolet wavelengths, e.g., CPF^® lenses (Corning Medical Optics) and Blublockers® (JS&A Distributors) which provide relief from the intensified effect of glare and the hazy vision associated with impaired vision, including individuals suffering from ARMD, their use by such individuals is insufficient to prevent the progressive loss of vision resulting from the effects of ARMD because of one or more of insufficient use of the eyeglasses in low intensity light situations, insufficient shielding of the eye from stray, unfiltered light and/or insufficient filtration of all of the protoporphyrin IX excitory wavelengths.

Objects of the Invention

It is an object of the invention, method for the amelioration of the visual degeneration of an individual with impaired vision or who is susceptible to impairment of vision as a result of ARMD. Another object is the provision of optical devices useful for the amelioration of the visual degeneration in an individual with impaired vision or who is susceptible to impairment of vision as a result of ARMD. Other objects will be apparent to those skilled in the art to which this invention pertains.

Summary of the Invention

In a method aspect, this invention relates to a method for the amelioration of the visual degeneration of an individual with impaired vision or who is susceptible to impairment of vision as a result of age-related macular degeneration (ARMD) , which comprises filtering macular damaging superoxide and/or singlet oxygen photogenerated by protoporphyrin IX or other hematogenous photosensitizers by the excitatory wavelengths from light entering the eye or eyes of the susceptible individual.

In an article of manufacture aspect, this invention relates to an ocular device for the treatment of ARMD and like blue light related ocular diseases comprising means to filter all of the light which enters the eye, including a lens adapted for transmitting light therethrough which filters the macular damaging superoxide and/or singlet oxygen generating protoporphyrin IX excitatory wavelengths from light entering through the lens the eye or eyes of an ARMD- susceptible individual wearing the device.

In a preferred article of manufacture aspect, the ocular device of this invention is in the form of an intraocular device adapted to be surgically implanted in an eye.

In another preferred article of manufacture aspect, this invention relates to an ocular device of this in¬ vention in the form of a contact lens adapted to be mounted temporarily on an eye.

In a further preferred article of manufacture as¬ pect, this invention relates to an ocular device of this invention in the form of eyeglasses which comprise a light-filtering lens, a frame holding the lens, and a facial contour adapting light shield surrounding the lens thereof which prevents unfiltered ambient light from reaching the eye when the eyeglasses are worn by an individual.

Brief Description of the Drawings Various other objects, features, and attendant advantages of the present invention will be more fully appreciated as the same becomes better understood when considered in conjunction with the accompanying drawings, in which like reference characters designate the same or similar parts throughout the several views, and wherein: Figure 1 are ESR spectra resulting from the irradiation of protoporphyrin IX after 2 minutes (Scan A) , after 30 minutes (Scan B) , and after 2 minutes in the presence of SOD (Scan C) ; Figure 2 are ESR spectra resulting from a 5-minute irradiation of protoporphyrin IX through a filter which filtered visible light to 405 nm (Scan A) , to 525 nm (Scan B) , and to 650 nm (Scan C) ;

Figure 3 are ESR spectra resulting from a 30-minute irradiation of protoporphyrin through a filter whi:^~h filtered visible light to 405 nm (Scan A) , to 525 nm (Scan B) , and to 650 nm (Scan C) ;

Figure 4 is a prior art (U.S. Patent No. 4,687,485) intraocular lens, modified to contain a blue wavelength filter in accordance with this invention; and

Figure 5 is another prior art (U.S. Patent No. 4,014,049) intraocular lens, modified to contain a blue wavelength filter in accordance with this invention.

Detailed Description of the Invention Experimental evidence has demonstrated that ARMD develops as a direct result of photosensitization of the choriocapillaris capillary endothelium and Bruch's mem¬ brane by superoxide and singlet oxygen generated by photoactive compounds in blood. Using electron spin resonance (ESR) spectrometry, the spin trap 5,5-dimethyl-l-pyrroline-l-oxide (DMPO) , and the singlet oxygen trap 2-(9,10-dimethoxyanthra- centyl)-t-butylhydroxylamine (DTBH) , it has been dem¬ onstrated that the photoactive compound protoporphyrin IX (PP IX) , a naturally occurring precursor molecule of hemoglobin found in erythrocytes and plasma, generates superoxide and singlet oxygen. The amount of reactive oxygen species produced by this system is dependent on the concentration of PP IX, and the intensity and the wavelength of light delivered. The production of these photooxidants is significantly reduced by filtering the excitatory wavelengths of PP IX.

These photogenerated oxidants damage the basement membrane of the vascular endothelium of the choriocapil- laris and Bruch's membrane, necessitating a reparative process. This results in thickening of Bruch's membrane, a feature consistently found beneath retinal^'pigment epithelial cells that have developed drusen. A thickened Bruch's membrane and possibly damaged basal cellular σrganelles impair the exchange of nutrients and waste products to and from the retinal pigment epithelium (RPE) . The RPE becomes progressively compromised, to the extent that it can no longer adequately support the outer retina. The dysfunctional RPE, unable to process rod outer segments, becomes inspissated, leading to drusen formation. The hypoxia induced in the outer retina because of the compromised RPE, may trigger release of angiogenic factors leading to subretinal neovascular proliferation.

In accordance with this invention, the prevention of phototoxic damage associated with this mechanism is prevented by protecting the vascular endothelium with appropriate filters which remove at least the protopor¬ phyrin IX exciting wavelengths from the light entering the eye of an individual suffering from progressive ARMD or who, by the presence of drusen, is suffering from the disease but has not yet experienced visual impairment as a result thereof.

Protoporphyrin IX (PP IX) is a precursor molecule of hemoglobin, which is found naturally in erythrocytes. In the disease erythropoietic protoporphyria, PP IX is known to be detectable in erythrocytes and serum. The histo- pathologic changes noted in vascular basement membranes of the light-exposed skin of patients with erythropoietic protoporphyria is remarkably similar to the changes noted in the endothelium of the choriocapillaris and Bruch's membrane of patients with age-related macular degenera¬ tion. PP IX has been demonstrated to photosensitize corneal endothelium by ion flux studies and scanning electron microscopy. Superoxide production by PP IX has been suggested as being responsible for producing the clinical manifestations of erythropoietic protoporphyria. In this study, the role of PP6 IX as a wavelength- dependent photogenerator of the reactive oxygen species superoxide, hydroxyl radicals, and singlet oxygen were investigated by electron spin resonance (ESR) spectrometry with spin trapping techniques. This tech¬ nique consists of using a nitrone or nitroso compound to "trap" an initial unstable free radical as a "long-lived" nitroxide, which can be monitored at room temperature using commercial electron spin resonance (ESR) . Infor¬ mation obtained from the hyperfine splitting of the spin trapped adduct can aid in the identification of the original free radical. The detection of photogenerated superoxide and singlet oxygen but not the hydroxyl radical by PP IX is strong evidence that photosensitization of the vascular endothelium and Bruch's membrane begins the cascade of events leading to ARMD. The wavelength-dependent production of these photooxidants demonstrates that an intervention with a filter which removes the PP IX-exciting wavelengths from the light entering the eye ameliorates or arrests the disease.

A contemplated equivalent of this invention employs the method or a device of this invention to prevent retinopathy of prematurity (ROP) , another disease affect¬ ing a population with compromised protective enzymes in- eluding, apparently, those for photogenerated superoxide and singlet oxygen from photosensitizing compounds, such as PP IX, in blood. The proliferating endothelium of the preterm infant appears to be sensitive to photooxidant products of blood, and because defensive enzyme systems are immature, significant capillary damage with vascular closure can occur by this mechanism.

Oxygen toxicity has long been correlated with the development of ROP. However, evidence has been presented that exposure to bright light in the hospital nursery may be a risk factor for the development of ROP. (Glass, P., et al., N. Engl. J. Med. 313: 401-404, 1985.) As a contemplated equivalent of this invention, inhibition of the development of ROP is achieved by protecting the eyes of the premature infant only from a damaging amount of the protoporphyrin IX exciting wavelengths of the light to which the eyes of the premature infant are exposed, e.g., for at least a period of time equivalent to the lost term of the pregnancy.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limita¬ tive of the remainder of the disclosure in any way what¬ soever. In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius; and, unless otherwise indicated, all parts and percentages are by weight.

The entire texts of all applications, patents and publications, cited above and below, are hereby incor¬ porated by reference.

EXAMPLES MATERIAL AND METHODS Reagents Protoporphyrin IX (PP IX) , diethylenetriamine- pentaacetic acid (DTPA) , superoxide dismutase (SOD) , catalase (CAT) , xanthine and xanthine oxidase were purchased from Sigma Chemical Company (St. Louis, Missouri). Triethylamine l,4-diazabicyclo[2.2.2]octane (DABCO) and methylene blue were obtained from Aldrich Chemical Company (Milwaukee, WI) . The spin trap 5,5-dimethyl-l-pyrroline-l-oxide (DMPO) was synthesized according to the method of Bonnett et al., J. Chem. Soc. 2094-2102, 1959. The singlet oxygen trap 2-(9,10- dimethoxyanthracentyl) -t-butylhydroxylamine (DTBH) was prepared as outlined in Keana et al., J. Org. Chem. 51: 3656-3462, 1986. All buffers were passed through a Chelex-100 (Biorad, Richmond, California) ion exchange column to remove trace metal ion impurities. Detection of Superoxide and Singlet Oxygen

In a darkened room, varying amounts of PP IX were suspended in either: (a) 50 mM sodium phosphate con¬ taining 1 mM DTPA at pH 7.4 to which DMPO (0.1 M) was added for the detection of free radicals; or (b) deion- ized water to which DTBH (200 μM) dissolved in DMSO (0.28 M) as included. In some experiments, SOD, CAT, triethylamine or DABCO were included. In all experi¬ ments, the final volume was 0.5 ml. The reaction mixture was then transferred to a quartz flat cell, fitted into the cavity of an electron spin resonance (ESR) spectrometer (Varian Associates Model E-9, (Palo Alto, California) and the signal was recorded at 20^βC. After this, spectra were recorded at specific time intervals following continuous irradiation of the solution in the spectrometer with a 150 watt halogen light source (Transilluminator model OS 3000, Medical Instrument Research Associates, Waltham, Massachusetts) . Narrow-band interference light filters (Edmund Scientific, Barrington, New Jersey) were placed in front of the light beam to select specific wavelengths of light for irradiation of the solution. ^' Light fluxes were measures with a spectroradiometer (E.G.&G., Gamma Scientific, Model DR 2550, San Diego, California) . The light source was placed at 6 cm from the sample.

A number of experiments required a continuous flux of superoxide was required, which was generated by the aerobic action of xanthine oxidase on xanthine. The rate of superoxide production was calculated by following the SOD-inhibitable reduction of ferricytochrome c, at 550 wm, using the extinction coefficient of 2lmM^"1cm^"1.

RESULTS

Spin Trapping with Continuous Irradiation

When PP IX (0.1 mM) suspended in 50 mM sodium phos- phate, pH 7.4, containing DTPA (1 mM) and DMPO (0.1 M) was irradiated (200 μE/m²/sec. ) , in ambient light"an electron spin resonance (ESR) spectrum corresponding to 5.5-dimethyl-5 hydroperoxy-1-pyrrolidinyloxy (DMPO-OOH) was observed. In the absence of all light, no spectrum was recorded. Because protoporphyrin is so sensitive to photoactivation that even low levels of either incan¬ descent or fluorescent lighting can lead to a "back¬ ground" spin trapping of superoxide, it was necessary to conduct all experiments in the dark.

Effects of Protoporphyrin IX Concentration. Light Intensity. Wavelength on Spin Trapping

The effects of light intensity and the concentra¬ tions of protoporphyrin IX on the generation of super¬ oxide were investigated. When the concentration of protoporphyrin IX was held constant, increased intensity of light exposure produced larger EPR spectra, i.e., more superoxide was generated. When the light intensity was held constant, at all concentrations of protoporphyrin IX (0.5 M-1.5 μli) , the ESR spectrum characteristic of DMPO-OH and not DMPO-OOH was recorded (Figure 3B) . Furthermore, at these concentrations a longer period of irradiation (30 minutes) was necessary to detect the EPR spectrum.

Finally, when both the concentration of PP IX (0.1 mM) and light intensity (8

) were held constant, light filtered at 405 nm produced consistently and significantly more superoxide anion detected as DMPO-OH, than either light filtered at 525 nm or 650 nm.

The EPR signals were inhibited by the addition of SOD (30 U/ml) (Figure 3C) , but not catalase (300 U/ml) . These data demonstrate that it was the superoxide and not the hydroxyl radical which was spin trapped by DMPO. Irradiation of DMPO (0.1 M) in the absence of PP IX did not yield any EPR signals.

Detection of Singlet Oxygen with DTBH When PP IX (0.1 mM) , suspended in water containing

DTBH (200 M) and DMSO (0.28 M) , was irradiated for 30 seconds the ESR spectrum corresponding to nitroxide II (2-(9,10-dimethoxy-anthracenyl)-t-butyl-nitroxide) was observed. Continued irradiation for 5 minutes resulted in an ESR spectrum characteristic of nitroxide endoperoxide III (2-(9,10-dimethoxy-anthracenyl-9, 10- endoperoxyl)-t-butyl-nitroxide) . Since superoxide is known to mediate the oxidation of hydroxylamines to nitroxides, a solution of DTBH in the presence of superoxide (5-10 M 0^"/min.) generated by the aerobic action of xanthine oxidase on xanthine, was illuminated and no ESR signal was detected. Furthermore, SOD (30 U/ml) and catalase (300 U/ml) had no effect on the ESR signal formed by the action of light on PP IX in the presence of DTBH. In contrast, addition of singlet oxygen quenchers such as 1.4-diazabicyclo[2.2.2]octane (DABCO) (10 mM) or triethylamine (20 μl) in the PP IX solution eliminated the nitroxide signal. Small characteristic ESR spectra produced from PP IX at physiological concentration (0.25 μM) were detected by comparing these spectra to those obtained from irradiation of control reaction solutions which contained no PP IX. As in the case of the detection of superoxide, light centered at 405 nm produced consistently and significantly more singlet oxygen than either centered at 525 nm or 650 nm. The ESR spectra consists of a mixture of nitroxides II and III. Irradiation of DTBH in the absence of PP IX did not yield any EPR signals.

In carrying out the method of this invention, the eyes (or eye if the vision of one eye has been lost) of an individual susceptible to loss of vision from ARMD is fitted with an ocular device which prevents light containing a macular damaging amount of the superoxide- generating protoporphyrin IX excitory wavelengths from entering the eyes of the susceptible individual. Macular degenerating amounts of such wavelengths can enter the eye as a result of one or more of failure of the ocular device to filter a broad enough spectrum of the light entering the eye, particular in the case of bright sunlight or fluorescent and incandescent light, or to prevent unfiltered light from leaking around the device into the eye, e.g., in the case of eyeglasses, or from the failure of the susceptible individual from wearing the device in relatively low intensity light situations, when sunglasses would ordinarily not be worn, e.g., in evening hours.

The amount of unfiltered or inadequately filtered light which will produce a macular damage depends, in part, on the susceptibility of an individual to macular damage. In a highly susceptible individual, virtually any amount of light which contains wavelengths in the visible range up to about 580 nm will produce some macular damage. In other less susceptible individuals, filtering the wavelengths up to about 520 nm from all bright sunlight, fluorescent light, and incandescent light, e.g., above about 100 μE/m/sec. , or filtering the wavelengths up to about 580 nm, only from light of an intensity above 10 μE/m²/sec. will suffice to prevent damage.

Susceptibility can be determined by measuring a concentration of superoxide and/or singlet oxygen in the eye after exposure of the eye to a defined amount of light consisting of or comprising about 400 nm wavelength. As would be apparent, the wavelengths closest to 400 nm are the excitatory to protoporphyrin IX and thus are the most superoxide and/or singlet oxygen generating. Thus, it is most important that visible light in the blue range up to 460 nm, preferably up to about 520 nm and most preferably up to about 580 nm, is filtered from all light entering the eye. Higher wavelengths are less excitatory and, therefore, from about 60 to 85%, preferably from about 70 to 95% and most preferably from about 85 to 95% of the light in the higher wavelengths up to about 620 nm, need be removed from light entering the eye, depending on the susceptibility to macular damage of the individual involved, to ameliorate macular degeneration.

Susceptibility to macular damage can be divided into three categories, viz., Type I individuals, who have drusen but no vision loss; Type II individuals, who have confluent drusen and moderate visual loss; and Type III individuals, who have macular degeneration with associated severe visual loss in one or both eyes.

Example 1: Contact Lens Prepare in the conventional manner a prescription or non-prescription contact lens from (a) a yellow "striking" or cut-off color CdS in K-Ca silicate base glass having a cut-off beginning at about 460 nm and reaching 20% transmission at about 425 nm (Schott Glaswerke Glass Type GG5, Mainz, Federal Republic of

Germany) ; from (b) a yellow "striking" CdSrCdSe in K-Zn silicate base glass having a cut-off beginning at about 525 nm and reaching 0% transmission at about 480 nm (Schott Glaswerke Glass Type GG74) ; from (c) an orange CdSrCdSe in a K-Zn silicate base glass "striking" glass having a cut-off beginning at about 625 nm and reaching 0% transmission at about 525 nm (Schott Glaswerke Glass Type 0G5) ; from (d) a red "striking" glass of the same chemical type as (c) having a cut-off beginning at about 650 nm and reaching 0% transmission at about 585 nm

(Schott Glaswerke Glass Type RG1) ; and (e) from a red "striking" glass of the same chemical type as (c) having a cut-off beginning at about 700 and reaching 0% transmission at about 650 nm (Schott Glaswerke Glass Type RG5) .

Instruct a Type I ARMD individual to wear the Example 1(a) contact lenses in diffused ambient low level or natural (foggy, rainy) light and to additionally wear sunglasses which absorb an additional portion of the blue wavelength spectrum in the higher wavelengths or to wear Example 1(b) contact lenses when exposed to sunlight or bright fluorescent or incandescent light. Instruct a Type II ARMD individual either to wear Example 1(b) contact lenses at all times and to supplement them with sunglasses which absorb the remaining portion of the higher blue wavelengths when in bright sunlight or bright fluorescent or incandescent light or to wear Example 1(c) contact lenses at all times. Instruct a Type III ARMD individual to wear at all times when exposed to any light containing blue wavelengths either contact lenses of Example (d) or Example (e) , depending on the degree of loss of vision and the susceptibility of the individual to further ARMD, or to wear the contact lens of Example (c) at all times when exposed to blue wavelength- containing light and supplement them with sunglasses which absorb the remainder of the wavelengths up to about 650 nm when exposed to bright natural or artificial light.

Example 2: Contact Lens

In accordance with the method described in U.S. Patent No. 4,390,676 formulate a corneal contact lens prepared from the following formulation:

Parts by Weight

Methyl methacrylate 95

Ethyleneglycol dimethacrylate 5 Bisazoisobutyronitrile 0.2

2,2'-dihydroxy-4,4'-dimethoxy- benzophenone (UV absorber) 0.5

Blue wavelength absorbing red and/or yellow dyes 0.002-0.010

Select the dyes and the concentrations thereof so as to achieve 0-10% transmission in the visible range up to about 460 nm or up to about 520 nm or up to about 580 nm or up to about 620 nm.

Mix all of the components of the formulation and pour the mixture into glass test tubes of about 1" diameter. Then place the tubes in an 80^βF bath until the mixture solidifies (approximately 3 days) . Then transfer the test tubes to an oven and subject them to increasing temperatures reaching a maximum of 105°C in 3 days. Then remove the test tubes from the ovens, allow them to reach room temperature, and break the glass, leaving polymerized plastic rods. Slice plastic discs about 1" in thickness off the rods and convert the discs into corneal contact lenses having a center thickness of 0.02 inches, outside diameter of 10 mm, base curve radius of 8 mm, and 0.045 gram average weight using conventional contact lens making equipment.

Example 3

Construct a conventional pair of sunglasses containing a lens produced from a glass of Example 1 or a plastic of Example 2 or a CPF^® 550 photochromic lens.

Surround the lenses, either directly on the circumference of each lens or on the frames (if the lenses are surrounded by a frame) with a strip of very soft foamed polyurethane or natural or synthetic elastomer of a shape and resilience which prevents all stray unfiltered light from entering the eyes when the sunglasses are worn. Instruct an ARMD individual to wear the sunglasses at all times when exposed to blue wavelength-containing visible light, alone or in conjunction with a contact lens of Example 1 or 2.

Example 4: Intraocular Device

Fabricate a pseudophakos 10 of Figure 5 having an intraocular optical section 12 having spaced chordal openings 16 and formed from a lens material which is biologically inert and contains U.V. and optical filter or filters which permit less than 10% and preferably 0% transmission of wavelengths up to about 520 nm, up to about 560 nm, or up to about 620 nm, and a fastening or haptic portion (lens-supporting arms 14) extending into openings 16 and permanently anchored in place at their proximal ends 18, with a light 20 therein, whereby it is looped reversely forward lens 12, with a U-shaped clip 22 having a relatively long strut-like portion 24 and shaped to accept the marginal portion of the iris of an eye. The biologically inert material forming the lens can be a methylmethacrylate resin, e.g., those available under the tradenames "Lucite" and "Plexiglass" containing the appropriate amount of a blue wavelength filter, e.g., a resin composition of Example 2, and the supporting arms are formed from a biologically ir . t material such as platinum, extruded polypropylene, polyamide, polycarbonate, or carbon fiber.

Example 5: Intraocular Device

Prepare an intraocular device of Figure 4 according to the procedure of Example 1 of U.S. Patent No.

4,687,485, except include in the liquid mixture used to produce the resin from which the lens body portion 1 is fabricated from 0.001 to 0.01 parts per 100 of the liquid mixture of red and/or yellow dyes which filter light passing through the lens body portion 1 up to about 460 nm, up to about 520 nm, up to about 580 nm, or up to 620 nm. Form the legs 2 and 3 so as to provide regions 8 and 9, respectively, which contacts the eye tissue between points 4 and 5 and points 6 and 7, respectively, of legs 2 and 3.

Mount a resulting lens absorbing to 460 nm in an aphakic eye of a Type I ARMD individual. Instruct the individual to wear sunglasses which absorb the remaining blue wavelengths at least to 520 nm and preferably to 580 nm when exposed to bright sunlight or artificial light. With a Type II ARMD individual, employ a lens which absorbs to 520 nm or 580 nm, the former with similar instructions with respect to wearing blue wavelength absorbing sunglasses. With a Type III ARMD individual, employ a lens absorbing to 580 nm or 620 nm, depending on the extent of loss of vision and the susceptibility to further ARMD.

The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and condi¬ tions.

Claims

WHAT IS CLAIMED IS:

1. A method for the amelioration of the visual degeneration in an individual who is susceptible to impairment of vision as a result of age-related macular degeneration (ARMD) , which comprises filtering the macular damaging amount of superoxide and/or singlet oxygen generating protoporphyrin IX excitatory wavelengths from the light entering the eye or eyes of the susceptible individual.

2. The method according to claim 1, wherein 95% of the light up to at least 520 nm are filtered from the light.

3. The method according to claim 1, wherein the wavelengths up to at least 580 nm are filtered from the light.

4. The method according to claim 1, wherein the lens is fitted in, on, or over the eye of the susceptible individual in a manner which prevents unfiltered light from entering the eye.

5. The method according to claim 4, wherein the lens filters substantially all of the ultraviolet wavelengths from light which passes therethrough and is surgically affixed to the eye.

6. The method according to claim 5, wherein the lens is an intraocular lens surgically implanted in any aphakic eye.

7. The method according to claim 6, wherein at least 95% of the wavelengths up to at least 620 nm are filtered from the light.

8. The method according to claim 4, wherein the lens is a contact lens fitted on the eye of the individual.

9. The method according to claim 8, wherein at least 95% of the wavelengths up to at least 620 nm are filtered from the light.

10. The method according to claim 1, wherein the lens is in a pair of eyeglasses fitted in a light-tight manner over the eyes of the susceptible individual.

11. The method according to claim 10, wherein at least 95% of the wavelengths up to at least 620 nm are filtered from the light.

12. An ocular device for the treatment of ARMD and like blue light related ocular diseases comprising means to filter all of the light which enters the eye, including a lens adapted for transmitting light therethrough which filters the macular damaging superoxide and/or singlet oxygen generating protoporphyrin IX excitatory wavelengths from light entering the eye or eyes of an ARMD-susceptible individual wearing the device through the lens.

13. An ocular device according to claim 12, wherein lens is adapted to be surgically affixed to the eye.

14. An ocular device according to claim 13, wherein the lens filters substantially all of the ultraviolet wavelengths from light which passes therethrough and is adapted to be surgically implanted in the aphakic eye.

15. An intraocular device according to claim 12, wherein the lens filters at least 95% of the excitatory wavelengths, including substantially all of the wavelengths up to at least about 620 nm.

16. An ocular device according to claim 12, in the form of a contact lens adapted to be mounted temporarily on an eye.

17. A contact lens according to claim 16, wherein the lens filters at least 95% of the excitatory wavelengths, including substantially all of the wavelengths up to at least about 620 nm.

18. An ocular device according to claim 12, in the form of a pair of eyeglasses which comprise a frame and a facial contour adapting-light shield surrounding the frame which prevents unfiltered ambient light from reaching the eye when the eyeglasses are fitted on the face of an individual.

19. An eyeglass according to claim 18, wherein the lens filters at least 95% of the excitatory wavelengths, including substantially all of the wavelengths up to at least about 620 nm.