Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Silicon containing doai
Reexamination Certificate
1999-06-21
2001-06-19
Travers, Russell (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Silicon containing doai
C514S068000, C424S450000
Reexamination Certificate
active
06248727
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to methods and materials for visualization or treatment of vasculature.
BACKGROUND OF THE INVENTION
Of the estimated 34 million people in the United States who will be age 65 or older in 1995, approximately 1.7 million will have some visual impairment resulting from age-related macular degeneration (ARMD). Approximately 100,000 of those affected will experience a devastating, rapid loss of vision due to choroidal neovascularization (CNV). (See, for example, U.S. Dept. Health and Human Serv., (1994) National Advisory Eye Council (1990-1992).) ARMD is the most common cause of vision loss in people over age 50 and, as the population ages, a greater number of elderly persons will become blind from ARMD than from glaucoma and diabetic retinopathy combined. Leibowitz et al. (1980) 24
Surg. Ophthalmol
. (suppl.) 335-610; Sorsby (1972) in:
Ministry of Health Reports on Public Health and Medical Subjects
(128th ed., London); Ferris (1983) 11
Am. J. Epidemiol
. 132-151.
Clinical research has shown that laser treatment of CNV reduces the risk of extensive scarring in selected cases of CNV characterized by a well-defined, predictable fluorescein angiographic pattern covering an area limited in size. Unfortunately, such “classic” cases comprise only 25% of the population with CNV, leaving 75% of the patients at risk of becoming blind from macular disease without the benefit of laser treatment. Moreover, the frequent (54%) recurrence of CNV is mostly attributed to incomplete angiographic visualization and subsequent inadequate treatment of CNV. Macular Photocoagulation Study Group (1986) 104
Arch. Opthalmol
. 503-512. The practical difficulty in detecting CNV clinically has been documented in a recent study involving clinical and pathological examinations of 30 eyes. In 57% of the cases, CNV was detected histologically but not clinically. Sarks (1973) 75
Br. J. Ophthalmol
. 587-594. This finding is in agreement with other histopathological studies in which CNV was detected in angiographically-unrecognized lesions. Bressler et al. (1992) 110
Arch. Ophthalmol
. 827-832; Small et al. (1976) 94
Arch. Ophthalmol
. 601-607.
As presently performed, the ability of fluorescein angiography to highlight CNV is limited by a number of factors. First, the dye rapidly fills both the retinal and choroidal vessels. Thus, visualization of small vascular beds, such as those typical of CNV, is often hampered by the lack of contrast caused by the bright fluorescence emanating from major choroidal vessels. Second, visualization of CNV is based on the leakage into and/or staining of tissue by the dye, which occurs only during a particular pathological stage. This process is not reliable because at certain stages of the disease, diseased vessels do not leak or stain. Also, metabolic waste products may accumulate in the vicinity of the lesion, decreasing the permeability or delaying the leakage into extravascular tissues. Third, when vessels leak, dye accumulates in the tissues surrounding the CNV lesion and actually masks its boundaries. Fourth, both the exciting and fluorescent light may be absorbed by subretinal blood, turbid fluid, pigment, or fibrous tissue, thereby reducing the intensity of the fluorescence emanating from the CNV. Bresler et al. (1988) 32
Surg. Ophthalmol
. 375-413; Bressler et al. (1991) 109
Arch. Ophthalmol
. 1242-1257.
Indocyanine green (ICG) angiography has been reportedly beneficial in some cases. Destro et al. 96
Ophthalmology
846-853. Because the excitation and emission wavelengths of this particular dye are longer than those of fluorescein, the light penetrates turbid media better, thereby eliminating the fourth limitation mentioned above. On the other hand, however, the enhanced penetration of light in ICG angiography aggravates the first-mentioned limitation of fluorescein angiography, i.e., interfering fluorescence, because large underlying choroidal vessels are visualized more effectively. Moreover, ICG angiography shares with fluorescein angiography the limitation of relying on leakage and staining of extravascular tissues. The poor understanding of the staining and pooling mechanisms of this dye hampers interpretation of angiograms.
The lack of adequate methods of angiographic visualization is unfortunate because clinical research has shown that laser treatment can reduce, in the long term, the risk of extensive loss of vision in classic CNV. (See, for example, Bressler et al. (1991) 109
Arch. Ophthalmol
. 1242-1257.) In-addition, the failure of laser photocoagulation has been attributed to inadequate identification of the entire extent of CNV and its location relative to the fovea.
As mentioned, CNV is commonly treated by laser photocoagulation in which a thermal scar is produced. The procedure typically causes a dramatic loss of vision when the fovea is treated. See, for example, Macular Photocoagulation Study Group (1991) 109
Arch. Ophthalmol
. 1220-1231. Nonetheless, the treatment is performed to prevent progressive visual loss. The cases eligible for treatment, which make up only 25% of the eyes with CNV, must be the well-defined “classic” type of CNV that is not too large. The remaining 75% of affected eyes are untreated because laser photocoagulation does not spare useful vision. In addition, new blood vessels recur in a majority of the patients (54%) treated with laser photocoagulation, thereby necessitating further scarring treatment. Other than the incomplete identification of CNV mentioned above, recurrence has been attributed to damage to Bruch's membrane and scarring, conditions known to predispose tissues to new blood vessel growth.
It is an object of this invention to provide methods and materials for selective occlusion of vasculature. That is, it is an object of this invention to provide for the occlusion of blood vessels without significant, concomitant damage to tissue surrounding and supplied by said blood vessels. It is another object of the instant invention to provide methods and materials for selective and non-invasive chemical occlusion of blood vessels and sinuses in the mammalian eye, especially blood vessels and sinuses of choriodal origin. It is a further object of the instant invention to provide methods for selectively and non-invasively occluding vascular abnormalities of the mammalian eye, such abnormalities being associated with macular degeneration and related clinical conditions involving neovascularization, such as choroidal neovascularization. It is still a further object of the instant invention to provide methods for non-invasively occluding vascular abnormalities associated with pathologies of the choriocapillaris such as choroideremia, gyrate atrophy, and acute placoid multifocal pigment epitheliopathy, as well as vascular abnormalities which are non-choroidal such as those associated with diabetes. It is yet another object of the instant invention to provide diagnostic reagents and diagnostic kits for selective, non-invasive chemical occlusion of vasculature. These and other objects and features of the invention will be apparent from the description, drawings and claims which follow.
SUMMARY OF THE INVENTION
The present invention provides a method of chemically occluding a blood vessel or blood sinus in a mammalian eye which involves: co-administering intravenously a fluorescent dye encapsulated within heat-sensitive liposomes and a tissue-reactive agent which is effective to cause chemical tissue damage following its activation; non-invasively heating tissue at a pre-determined anatomical locus within the eye so that the heat-sensitive liposomes leak and release their contents into the blood vessel or sinus at the pre-determined locus; exciting the fluorescent dye; visually observing a pattern of fluorescent vasculature which develops at the pre-determined locus; and, activating the tissue-reactive agent disposed within the blood vessel or sinus so that the blood vessel or sinus is chemically damaged to an extent sufficient to occlude the vessel or sinus
Testa Hurwitz & Thibeault LLP
The Johns Hopkins University
Travers Russell
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