JP2003506394A - Method for increasing optic nerve, choroid and retinal blood flow to facilitate retention of vision - Google Patents

Abstract

(57) Summary The present invention relates generally to the field of ophthalmic pharmaceuticals. More specifically, the present invention relates to methods for treating eye disorders and maintaining eye health. The present invention more particularly relates to direct or cyclic-GMP synthesis of an effective amount of a composition containing an agent that increases the level of cyclic-guanosine monophosphate (cyclic-GMP). Improve visual function and increase blood flow therein by improving optic nerve and optic nerves through application, either by stimulating or by inhibiting cyclic-GMP selective phosphodiesterase (s). Methods for optimizing retinal health.

Description

Detailed Description of the Invention

BACKGROUND OF THE INVENTION The present application is a provisional patent application number 60/148, filed August 10, 1999.
, 150 claims priority. The entire text of the above-mentioned disclosure is hereby incorporated by reference in detail without refusal.

1. Field of the Invention The present invention relates generally to the field of ophthalmic pharmaceuticals. More particularly, the present invention relates to methods for treating eye disorders and maintaining eye health. The present invention more particularly relates to the effective or direct or cyclic-GMP synthesis of compositions containing factors that increase cyclic-guanosine monophosphate (cyclic-GMP) levels. Through application, either by stimulating or by inhibiting cyclic-GMP selective phosphodiesterase (s), improves optic function and increases blood flow therein to increase optic nerve and It relates to a method for optimizing the health of the retina.

2. Background Information In general, visual processes are involved in complex pathways to the brain. To see, light must enter through the cornea and lens; penetrate deeply into the back of the eye through the retina; pass through ganglion cells and bipolar cells; then synaptic vesicles, inner fibers, nuclei, external Fiber, end bar (t
erminal bars), transmitted through the cilia to the outside of the reticular layer; and finally reach the photoreceptors. Photoreceptors can be considered to perform instant film processing of visible light. After the light rays are processed in the photoreceptor discs, the light rays are cilia, ellipsoids, myoid bodies, Muller cells,
It passes back through the outer fibers, nuclei, inner fibers, synaptic vesicles, outer plexiform layer, inner nuclear layer, bipolar cells, inner plexiform layer, and finally reaches ganglion cells. Here, the light rays are processed into axon signals. After it reaches the ganglion cells, the signal is transported to the brain through the optic nerve fibers. Here it is evaluated and combined by visual cerebral lobes to form a visual image. The unobstructed signal is carried by the retina, and the tips of the optic nerve and optic nerve fibers are considered to be the most important parts of the process for creating visual images. Sufficient blood flow nurtures tissue through this pathway, thus ensuring axon flow.

It is understood that the human eye (and indeed the structure of most mammalian eyes) has two large and distinct circulatory systems (the retina and the uveal tract).
The retinal circulation is calculated to account for only about 2% of all ocular circulations, but this 2% is important for the health of the ocular nerve connections to the brain. That is, 1.2 million axons, which create the nerve trunk, are known as the optic nerve. The cell bodies containing the genetic material and metabolic machinery for this connection are all located in the inner layers of the retina and of their blood supply from the locally autoregulated retinal circulation. Drive virtually all (ie, including energy, oxygen / carbon dioxide, and metabolic by-product exchanges). Any significant compromise on retinal circulation
Typically achieved by loss of vision.

On the other hand, much of the internal circulation of the eye passes through the uveal system, a sponge-like, dilated vessel tangle, which is located behind the retina and in the epithelium of its pigment. This vascular bed provides a rich source of nutrients for metabolic activation of the photoreceptors of the exterior of the retina and of the pigment epithelium that supports them. In addition, this seemingly excess blood supply acts as a heat sink, absorbing heat energy from the focused light that could otherwise damage nerve tissue. The choroidal circulation (the part of the bed of uveal vessels that immediately follows the retina) has some local regulatory properties, but this also leads to stimuli that are not necessarily produced in the eye itself. Supplied with autonomic nerves that can respond to major changes in circulating volume.

To undertake the velocity of blood flow in the retina and optic nerve, it is to understand that the retina is essentially a specialized part of the brain, and its circulation is very tightly regulated. is important. Blood flow through the brain is typically constant in healthy individuals whether they are running a marathon or sleeping. Clearly, enormous variations in carotid blood inflow pressure into the brain occur throughout a typical day, and angiogenesis in the cerebral cortex responds by regulating its tolerance. This is accomplished by the contraction or expansion of blood vessels through the brain. When the pressure of the cerebrospinal fluid is increased, it effectively creates a bed of solid blood vessels in the cerebral cortex and is inflated to diminish the intrinsic resistance of blood vessels in the brain, thereby Maintains a constant blood flow. This process is called autonomic regulation.

Autonomous regulation in the retina is similar to that found in the brain. Therefore, when the intraocular pressure is reduced, the circulation in the retina is not always increased. This is a consistent feature of the example of hyperventilation (carbon dioxide exhalation (blo
w off), thereby reducing circulation to all of the eye's native blood vessels), and as treatment with latanoprost (increasing clear fluid flow outside the eye) . Both of these result in a significant reduction in intraocular pressure, but visual function can actually be reduced at the same time.

Circulation within the retina is also highly pH dependent. Experiments in which various gases were introduced into the bloodstream through the respiratory system showed that as CO ₂ levels increased and pH decreased, circulation to the retina was typically observed during breathing in the atmosphere. Clearly demonstrated to be increased by up to 40% above the basal level. Conversely, pure oxygen breathing causes a significant reduction in circulation in the retina. This latter response is
It may be due to post lens fibroplasia, or part of the disease process known as premature retinopathy. This causes total or partial blindness in many premature babies.

In the healthy eye, due to the relatively abundant blood vessels of the choroid, a fairly large change in choroidal blood flow can be achieved with minimal change in visual function. However, since the uveal circulation comprises a significant portion of the ocular volume, a substantial reduction in choroidal blood flow is generally achieved by a significant reduction in intraocular pressure. Thus, for example, during hyperventilation, the exhalation of the natural vasodilator carbon dioxide, diminishes both choroidal and retinal circulation side by side, and correspondingly reduces visual function. descend. Typically, individuals with a large decrease in intraocular pressure as a result of hyperventilation have a very large loss of visual function.

Thus, it is clear that blood flow in the retina and around the optic nerve plays an important role in many ocular disorders. The new technique is facilitated by a description of the posterior features of the eye, as well as evaluation of circulatory, metabolic, and hematological factors, thereby improving the determination of the cause of various eye diseases. In turn, various therapeutic agents can cause specific ocular disorders, more particularly, their progression being weakened, alleviated, or reversed by improving ocular circulation. Can be applied to more accurately undertake the pathophysiology underlying the disorders of

For example, other researchers have found that cyclic 3 ′, 5′-adenosine monophosphate (c
The drug was used to stimulate the production of AMP), thereby lowering intraocular pressure and increasing ocular circulation. It is well known that β-adrenergic stimulation in some tissues is mediated intracellularly by the second messenger cAMP. cAMP is produced from ATP by the membrane-bound enzyme adenylate cyclase. It is believed that cAMP also activates steps in a series of processes leading to protein phosphorylation and eventual biological activity. The cAMP process is generally considered to be a short duration process. This is because cAMP is rapidly and efficiently degraded intracellularly by the abundant presence of cAMP phosphodiesterase.

The pathway by which cAMP is produced is extremely complex. cAMP is produced when adenylate cyclase is activated through activation of many receptors.
This stimulation is mediated by G _{s and} by inhibition of at least one other protein belonging to the G _i class of G proteins. It is known that there are at least 10 tissue-specific adenylate cyclase isozymes, each with a unique pattern of regulatory response. Some of these isoenzymes are inhibited by the G protein βγ subunit. Others are α of G _s
When stimulated simultaneously by the subunits, they are stimulated by these subunits. Others are stimulated by the Ca ²⁺ or Ca ²⁺ -calmodulin complex. Adrenergic drugs mediate the production of cAMP, thereby lowering intraocular pressure and increasing vascular blood flow.

[0013] Generally, diseases that may be sensitive to treatment with factors that can regulate blood flow in the eye include, but are not limited to, optic nerve disease, retinal disease, or choroidal disease. . More specific disorders include, but are not limited to, macular edema or macular regression. For example, macular edema is defined as swelling into the retina in the crucial central visual area of the posterior foramen of the eye. The accumulation of fluid tends to split neural elements of the retina from another and from their local source of blood, thereby creating a resting state of visual function in that area. Usually, this process is self-regulating, but occasionally persistent visual impairment is caused by macular edema. Often, swelling can take months to clear. The exact mechanism by which swelling is triggered is not clear, but perhaps certain neurometabolic toxins may play an important role in the disease process. Macular swelling also follows artificial lens implant insertion and a variety of cataracts, especially when there is a tear in the lens capsule that separates the glassy gel from the anterior chamber filled with liquid. Can occur. Prolonged macular edema after cataract surgery is one of the most frustrating dilemmas in all of ophthalmology and is extremely common. Macular edema is a common and fearing eye problem. Thereto, useful forms of eye treatment have not been previously known. The two types of cystic macular edema are: (a) without vascular leakage: pigmentation of retinitis, and other pigmented retinal degenerative disorders of the retina, early-stage macular holes, And choroidal neovascularization; and (b) with vascular leakage: diabetic retinopathy; occlusion of branched retinal veins; interstitial uveitis; and idiopathic retinal telangiectasia.

Another even more common chronic condition is macular regression. Instead of fluid accumulation outside the retina, excessive accumulation of the metabolic waste product lipofuscin tends to accumulate between the photoreceptors and the villus of the retinal pigment epithelium. These accumulations are
They grow progressively, and in their early pathological period, create discrete accumulations known as drusen. Lipofuscin is believed to accumulate as a result of photoreceptor element breakage. The abandonment of the cellular components of photoreceptors is consistently present in the healthy retina. Good retinal color epithelial metabolism generally ensures rapid removal of such visual catabolic byproducts. This accumulation of waste material slows the interaction between the retina and the pigment epithelium of the retina. This interaction reaches the nutrients and through which the catabolites are washed,
This establishes a semi-permanent cycle of catabolite accumulation. Accumulation is
Not only does it block the migration of metabolites between the retina and the pigment epithelium of the retina, they actually continue to undergo photoresponsive metabolism and are capable of accurately reducing NADH with no consistent advantage. Weaken.

Improved local circulation can delay or prevent the accumulation of lipofuscin, and interrupt the cycle of progressive block and elimination of metabolites that pass into or out of the retina. As a large number of drusen accumulate and initiate adhesions, most areas of the retinal photoreceptors may be permanently released from the retinal pigment epithelium villi near them. The portion of the retina so affected becomes blind. Unfortunately, the greatest trend in the aging population is to accumulate in the macula, a very central area of vision for drusen. Thus, macular regression is the most common cause of adult blindness in the United States and Europe. Macular edema generally affects only one eye, but macular regression is typically associated with both eyes and is usually fairly symmetrical in its appearance and progression. The problem is about growth and is expected to continue to grow.

Apparently, normal metabolism tends to produce catabolic waste products with the accumulation of protons and CO ₂ . Many chronic diseases of eye tissues tend to stagnate local metabolism, and normal catabolites (which "mobilize" otherwise increased local circulation. ) Is not actually produced. Instead, tissue breakdown products accumulate, thereby giving rise to false cycles of decay without replenishment. Therefore, various factors that may enhance local circulation in this setting may support defined tissue breakdown products and stimulate restoration of normal metabolic function.

SUMMARY OF THE INVENTION The present invention provides for increased ocular blood flow, perfusion, and / or circulation by
Methods are provided for treating diseases of the optic nerve. Ocular blood flow is generally improved by applying a pharmacologically effective amount of a factor that enhances vascular blood flow in the eye, either directly or systemically to the eye. As used herein,
The phrase "factor that enhances blood flow in the blood vessels of the eye" refers to a factor that increases cyclic-GMP analog, a factor that inhibits cyclic-GMP phosphodiesterase (s) (PDE), a factor that increases the activity of guanylyl cyclase, Click-GMP
Or a factor that increases the level of nitric oxide (NO) in the tissues of the eye. For example, factors that either enhance NO production or increase NO availability or lifespan, thereby activating guanylyl cyclase, increase cyclic-GMP levels, and Cause an increase in blood flow.

In a preferred embodiment, the optic nerve disease to be treated includes normotensive depressed optic neuropathy, ischemic optic neuropathy, toxic optic neuropathy, traumatic optic neuropathy, or idiopathic optic neuropathy. However, it is not limited to these. Examples of normotensive depressed optic neuropathy include primary ocular atrophy, ocular ischemic syndrome, shock-related ocular atrophy, or chronic systemic hypotension. Examples of ischemic optic neuropathy include anterior ischemic optic neuropathy, posterior ischemic optic neuropathy, giant cell arteritis, or Foster-Kennedy syndrome. Examples of toxic optic neuropathy include drug-induced optic neuropathy or nutritional optic neuropathy. Examples of traumatic optic neuropathy include inflammatory optic neuropathy, or optic retinitis. Examples of idiopathic optic neuropathy include optic nerve drusen or benign increased intracranial pressure. In a particular aspect of the invention, multiple optic nerve disorders occurring in the same patient are treated using the compositions and methods of the invention.

Alternatively, the invention provides for the administration of a composition containing a factor that enhances vascular blood flow in the eye to a patient suffering from a disease of the retina, or to an affected eye. By directly applying the composition, a method is provided for treating a disease of the retina. In a particular aspect, the retinal disease treated can be retinal neovascularization, ischemic blood / blood flow disorders, or toxic macular disease. Examples of retinal neovascularization include diabetic-associated forms of retinal neovascularization, abnormal hemoglobinopathy, or inflammatory vessel narrowing. The diabetic-related form of retinal neovascularization can be, for example, diabetic macular edema, ischemia, and neovascularization, or nonproliferative diabetic retinopathy. An example of abnormal hemoglobinopathy is the sickle cell constitution. Examples of inflammatory vessel narrowing include lupus, collagen vascular disease, HIV retinopathy, CMV retinopathy, or sarcoidosis. Examples of ischemic blood / blood flow disorders include central retinal vein occlusion or bifurcated retinal vein occlusion. Examples of toxic macular disease include drug-related macular disease, or chloroquine retinopathy. In certain aspects of the invention, multiple retinal disorders present in the same patient are treated using the compositions and methods of the invention.

In certain other preferred methods of the invention, the choroidal disorder is administered to a diseased eye a therapeutically effective amount of a composition containing at least a first factor that increases ocular blood flow. Treated by applying. Examples of choroidal disorders include posterior choroidal ischemic injury, degenerative subretinal neovascularization, diabetic choroidal ischemia, inflammatory subretinal neovascularization, or age-related choroidal ischemia. Examples include, but are not limited to: Examples of posterior choroidal ischemic disorders include degenerative drusen of the macula (ie, dry age-related macular degeneration), macular retinal pigment epithelium atrophy, and retinal pigment epithelium detachment. . Degenerative subretinal neovascularization is wet age-related macular degeneration. Examples of choroidal ischemia due to diabetes include choroidopathy due to diabetes. An example of inflammatory subretinal neovascularization includes the putative ocular histoplasma syndrome. Examples of choroidal ischemia that is not age-related include myopic regression or advanced myopia. In certain aspects of the invention, multiple choroidal disorders present in the same patient are treated using the compositions and methods of the invention.

Of course, patients often are present with multiple forms of any of the above diseases, and the compositions and methods described herein treat multiple disorders in the same patient. Is effective for. For example, the compositions and methods described herein are useful for treating patients suffering from optic nerve disorders and retinal disorders.

The method of the present invention further comprises macular edema, macular degeneration, drusen, macular disorders associated with hypertension, hemangiomas, papillitis, optic neuroretinitis or pigmentary retinal degenerative disorders,
It is effective in treating macular disorders such as toxic macular disease and macular disease secondary to rheological abnormalities. The method of the invention is with or without leakage of blood vessels,
Useful for treating macular edema. As an example of macular edema without leakage of blood vessels,
These include retinitis pigmentation, pigmented degenerative degeneration of the retina, early stage macular holes, or choroidal neovascularization. Examples of macular edema with vascular leakage include diabetic retinopathy, occlusion of branched retinal veins, interstitial uveitis, or idiopathic retinal telangiectasia. The methods of the invention can also be used to inhibit or prevent lipofuscin accumulation in the eye.

In the method of the invention described above, the factors included in the composition are
Cyclic-GMP analogs, compounds that inhibit cyclic-GMP PDE (s), compounds that activate guanylyl cyclase, or compounds that increase cyclic-GMP levels. Preferred cyclic-
Examples of GMP analogs include 8-bromoguanosine-3,5-cyclic monophosphate. Preferred agents that inhibit cyclic-GMP PDE (s) include sildenafil citrate, dipyridamole, zaprinast, filaminast, denbuphylene, picramylast, or zardaverine, carboline derivatives, pyridocarbazole derivatives, or quinazolinone compounds. In certain preferred aspects, the PDE inhibitor is type 5 PDE.
(PDE5) or PDE type 6 (PDE6). Preferred factors that activate guanylate cyclase (by increasing the level of NO) include sodium azide, sodium nitrate, hydroxylamine, hydrazine, nitroglycerin, nitroprusside, nitrosoureas, or nitrosamines. By activating guanylyl cyclase, these factors also increase cyclic-GMP levels. The NO level is also
It can also be augmented by NO donors or NO synthase stimulators, and such compounds are useful in compositions for use in the methods of the invention.
Preferred NO donors include sodium nitrosoprusside, nitroglycerin,
SIN-1, isosorbide mononitrate, isosorbide dinitrate, diethylenetriamine / NO, glycerol trinitrite
, Pentaerythrityl tetranitrito, mannitol hexanitrito, inositol hexanitrito, or propacyl nitrate. Preferred NO
2-Aryl-β-thiophene can be mentioned as a stimulating factor for the synthase. Other preferred compounds include nitrosated and / or nitroxylated PDEs
Examples include inhibitors, or polymeric materials that release NO. Combinations of two or more of the factors listed above are also contemplated in particular aspects of the invention.

Preferred methods of application include oral and parenteral administration, including ophthalmic, transdermal, pulmonary, nasal, buccal, or sublingual. More specifically, the compositions may be administered by the method of solutions, gels, semisolids, suspensions, metered dose devices, transdermal patches, or films.

Another aspect of the invention provides a kit for the treatment of ocular disorders, which comprises: Containing a composition containing a factor that enhances blood flow in the blood vessels of the eye. A sealed container, and instructions for administering the composition to a patient suffering from an eye disorder. As a result, blood flow in the patient's eye is increased. Compositions included in the kits of the invention include factors such as those described above.

The present invention also provides effective treatments for maintaining eye health, as well as various other ocular conditions in the retina and choroid of the eye and by improving blood flow in the eye around the optic nerve. Provide effective treatment of.

In addition to the above instructions, the present invention has normal vision for the purpose of increasing visual function, including but not limited to visual acuity, contrast sensitivity, and peripheral light sensitivity. Administration of the compositions described herein to a subject is contemplated.

Detailed Description of the Preferred Embodiments 1. Enhanced Blood Flow for Treatment of Ocular Disorders Surprisingly, there are numerous factors that enhance blood flow to and around the optic nerve. It has been found to be useful in treating eye disorders. It is known that relatively large changes in choroidal blood flow can be achieved with minimal changes in visual function. However, the retinal circulation is regulated very tightly in the brain. Most of the internal circulation of the eye passes through the uveal system, which lies behind the retina and its pigment epithelium. The choroidal circulation is the part of the bed of blood vessels that immediately follows the retina and contains the autonomic nerves that can produce major changes in the circulatory capacity in response to stimuli. It can be generated in or out of the eye.

Although the visual process is extremely complex, the signals carried by the retina, optic nerve tips, and optic nerve fibers are considered to be the most important parts of this process. Proper blood flow nurtures tissue through this pathway and ensures signal transduction. It is known that many ocular disorders include blockages or disorders of several types of ocular blood flow.

The human choroid, which supports metabolic functions outside the retina, is a dilating tissue, similar to certain aspects of the corpus cavernosum of the penis. The fenestrated choroidal vessels are highly responsive to both local and neural stimuli, and the uveal system, of which it is a part, provides up to 98% of the blood volume in the eye Can hold. It has recently been reported that choroidal blood flow reduces macular degeneration, the leading cause of congenital blindness in North America. We have determined that factors that can regulate ocular blood flow are of therapeutic value in the treatment of disorders in the area of the choroid, retina, and axons. This provides that enhanced circulation can be achieved without debilitating metabolic damage or vascular leakage.

There are a number of eye disorders in which increasing blood flow in the eye is beneficial. The methods of the invention include the step of administering to a patient suffering from such an ocular disease state a factor that increases ocular blood flow. Table 1 shows a number of disease states that would benefit from treatment using the methods of the invention.

[0032]

[Table 1] As shown in Table 1 (not intended to be exhaustive), there are generally three broad categories of ocular disease states that benefit from increased ocular blood flow. These are optic nerve diseases, retinal diseases, and choroidal diseases.
Within these general categories, there are numerous additional categories, including the more specific examples provided for illustration. Of course, those of skill in the art understand other disease states in which ocular blood flow is a factor that would benefit from treatment using the methods of the invention. The advantages of the present invention are described in more detail below using, for exemplary purposes only, the particular type of choroidal disease, age-related macular degeneration. It is understood that the methods and compositions of the present invention are useful in treating any ocular disease state.

Age-related macular degeneration (ARMD) is the leading cause of visual loss among Americans over the age of 60. As the macula degenerates, central reading vision declines, while peripheral vision is rarely affected. There are two forms of ARMD: dry or atrophic ARMD and wet or exudative ARMD. Wet ARMD is associated with abnormal blood vessel growth (subretinal neovascularization) and ARM
It is responsible for the high proportion of the most severe visual disruptions faced among D patients. However, wet ARMD accounts for only 10% of ARMD cases. Due to its dramatic pathological course, wet ARMD has received tremendous attention, and numerous treatment modalities have been devised to alleviate this form of disease, most of them laser or other. By means, it is directed to destroying leaking blood vessels that have been compromised. Dry ARMD is much more common,
It progresses more slowly and accounts for 90% of ARMD cases. Dry AR
The abundant cases of MD make up a high proportion of individuals legally declared blind in the United States, Europe, Australia, or parts of Asia. In addition, a high proportion of wet ARMD cases begin as dry ARMD. Despite the long-term need for effective treatments for dry ARMD, there were no treatments available prior to the present invention.

Blood circulation through the underlying blood vessels of the retina in the choroid is impaired in patients with ARMD (Pauleikboff et al., 199).
0; Chen et al., 1990; Giovannini et al., 1994; Grunwa.
ld et al., 1994; Friedman et al., 1995; Ross et al., 1998; C.
iulla et al., 1999; Dontsov et al., 1999). This decrease in circulation is due to the choroid providing the only source of nutrients for photoreceptors outside the retina and the only means for eliminating waste products, and this reduction in circulation is the most metabolically active tissue of the body. Can have an extreme effect on the macula, which is one of the

In ARMD, lipofuscin accumulation and aggregation of decay products derived from the outside of the retina occur in the space between the retinal photoreceptors that form the finger-like structure and ciliated pigment epithelial cells. The retinal pigment epithelium (RPE) is an essential metabolic factor. this is,
It regenerates photopigments and undertakes many important support and transport processes, thereby maintaining retinal function. The outermost layer of the anatomical sandwich that supports retinal function is the choroid, a highly vascularized tissue that nourishes and clears the catabolites from this highly active tissue complex. Is. Lipofuscin builds a space between the RPE and the choroid in diseased eyes. Fragments of incompletely disintegrated lipofuscin-bound dye, which accumulate in this space in ARMD, constantly occupy and pass through the choroid to the RPE even in the absence of light. Energy is oxidatively discharged (Sponse
l et al., 2000). Thus, once established, ARMD tends to follow a terrible pathological spiral, thereby selectively affecting the macula, the area of greatest metabolic activity.

Retinopathy due to wet ARMD, myopic degeneration, or diabetes, another major cause of blindness, is characterized by abnormal blood vessel formation after or in retinal material. New abnormal blood vessels, which are typical of these conditions, proliferate through the action of locally released hormonal factors. Hormonal factors are released in response to the weakened circulation inside the eye. Such blood vessels are only maintained after they are formed, still by maintaining an improperly sustained circulation in the surrounding tissue. Normalization of the equilibrium between metabolic tissue demand, nutrient supply, and clearance of catabolic metabolites results in abnormal leaky and potentially blinded blood vessel regression. Accordingly, the methods and compositions of the present invention that increase blood flow in the retina and choroid are expected to benefit in treating the late stages of retinal disorders due to wet ARMD and proliferative diabetes. In addition, timely treatment of individuals at risk of preproliferative diabetes and dry ARMD prevents the progression of these diseases to the angiogenic stage, as described herein. Is expected.

2. Factors that enhance blood flow The present invention aims to increase eye blood flow (especially in the retina of the eye) to maintain eye health and in their etiology. It is based on the discovery that it is a safe and effective method for treating various ocular disorders that have inappropriate vascular blood flow, such as macular edema and macular degeneration. The exact theory is not fully understood, but there is an improved (into and into the retina and choroid of the eye (
Blood flow (i.e. increased) can greatly improve the health of the retina and optic nerve, which in turn effectively prevents macular edema, macular degeneration, and other ocular disorders.

It is known that the enzyme guanylate cyclase catalyzes the conversion of guanidine triphosphate (GTP) to cyclic-GMP. Activation of guanylyl cyclase increases cyclic-GMP levels. Murad et al. Used nitrogen-containing compounds (eg, sodium azide, sodium nitrite, and hydroxylamine) to activate guanylate cyclase, and these compounds were active intermediates. It was discovered that it was converted to some nitric oxide (NO). Nitric oxide is directly involved in the activation of guanylate cyclase and the subsequent conversion of GTP to cyclic-GMP. Thus, factors that activate guanylate cyclase through the formation of the intermediate NO, thereby increasing NO levels and subsequently increasing cyclic-GMP levels, and increasing ocular blood flow are of the present invention. It is particularly useful in the method. The compositions of the present invention may include one or more agents that activate guanylate cyclase.

As described above, cyclic-AMP is also known to increase vascular blood flow. However, it operates through a pathway that is significantly different than that of cyclic-GMP. Briefly, certain adrenergic drugs mediate the production of cyclic-AMP, thereby reducing intraocular pressure and increasing vascular blood flow. Thus, this mechanism of action is significantly different from the pathway that follows cyclic-GMP in stimulating blood flow in the ocular blood vessels, as described herein.

Moreover, although factors that activate guanylate cyclase (eg, sodium azide, sodium nitrite, or hydroxylamine) have been described above,
Other factors that activate guanylate cyclase, increase NO levels, and / or increase cyclic-GMP levels also increase ocular blood flow and improve vision. Other guanylate cyclase activators include hydrazine, nitroglycerin, nitroprusside, nitrosoureas, or nitrosamines.

Factors that increase NO levels include those that are donors of nitric oxide and stimulate nitric oxide synthase or increase nitric oxide availability or longevity. Agents that stimulate nitric oxide synthase are described, for example, in US Pat. No. 5,811,437 (incorporated herein by reference)) 2-aryl-β-thiophene or other Compounds such as those described in US Pat. No. 5,478,946 (incorporated herein by reference). Factors that are donors of nitric oxide are sodium nitroprusside, nitroglycerin. , SIN-1, isosorbide mononitrate,
Isosorbide dinitrate, diethylenetriamine / NO, glycerol trinitrite, pentaethyltrityl tetranitrite (pentaerytrit
yl tetranitrite), mannitol hexanitrite, inositol hexanitrite, or propatil nitrate. Other compounds useful in the compositions of the invention include nitrosated / and nitrosylated PDE inhibitors (eg, described in US Pat. Nos. 5,958,926 and 5,874,437). (Each of which is incorporated herein by reference), or a polymeric material that releases NO (eg, US Pat. Nos. 5,994,444 and 5,770,645). Has been (
Each of which is incorporated herein by reference))). The compositions of the present invention may include more than one factor that increases NO levels.

It is also known that inhibition of cyclic-GMP PDE (s), especially inhibition of type 5 and 6 PDEs, promotes increased levels of cyclic-GMP (cGMP). is there. This in turn promotes increased blood flow in the uveal system. It is characterized by an increased velocity of blood flow in the retina and in the tissues surrounding the optic nerve. Therefore, cyclic-GMP PDE
Agents that inhibit (s) are also useful in the methods of the invention.
The compositions of the present invention may include more than one inhibitor of cyclic-GMP PDE (s).

Zaprinast and dipyridamole are both known to be inhibitors of the PDE family of type 5 and are therefore expected to act in the methods of the invention to increase ocular blood flow. Other PDE inhibitors useful in the methods of the invention include filaminast, denbuphylene, piclimalist, pentoxifylline, carboline derivatives (e.g., described in U.S. Patent No. 6,043,252 (see herein). Incorporated herein by reference)), pyridocarbazole derivatives (eg, US Pat.
No. 18,046 (incorporated herein by reference))
, Or a quinazolinone compound (eg, described in US Pat. No. 6,087,368, incorporated herein by reference).

It is also understood that the compositions of the present invention may include combinations of any of the above factors.

The following more detailed discussion of compounds that are particularly preferred for use in the methods of the invention are provided for illustrative purposes only and are not meant to limit the scope of the invention. One of ordinary skill in the art will recognize that the above-listed factors and other similarly acting factors are useful in the methods of the invention.

Particularly preferred compounds for use according to the present invention are sildenafil (sildena).
fil) (preferably citrate). Sildenafil is known to cause smooth muscle relaxation and increase blood flow, and is a selective inhibitor of cyclic guanosine monophosphate (cGMP) -specific PDE 5 (PDE5). Sildenafil citrate is 1- [3- (6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazole [4,3-d] pyrimidin-5-yl) -4-ethoxyphenyl. ] Chemically represented as sulfonyl-4-methylpiperazine citrate and having the following structural formula:

[0047]

[Chemical 1] Sildenafil citrate has a water solubility of 3.5 mg / mL in water, and 66
White to off-white crystalline powder with a molecular weight of 6.7. Sildenafil citrate is most recently utilized as a base for the oral treatment of erectile dysfunction and is sold by Pfizer Labs under the registered trademark Viagra®. Publications regarding sildenafil's benign visual side effects (eg, blue shift in vision, photosensitivity, and smearing reported to occur in some patients) allow FDA to insert a warning letter into its products. Strongly demanded.

Despite these side effects, we hypothesized that sildenafil may be therapeutically beneficial in the proper setting. Elevated cyclic-GMP levels (potent vasodilators) are brought about by the effect of sildenafil on PDE activity. This mechanism (ie PDE for intracellular cyclic-GMP)
By recognizing the local effects of inhibitors) and possible centrally mediated effects of neurogenesis, we suggest that sildenafil may possibly mediate a significant increase in choroidal blood flow. I gave a reason. Therefore, changes in visual and ocular blood were evaluated among a dozen clinical volunteers before and after ingestion of a single 50 mg oral dose of sildenafil. It was revealed that both choroidal circulation and high-resolution central visual function were substantially increased by oral sildenafil.

Significant increase in pulsatile ocular blood flow (+ 29%; 916 +/− 103 to 1)
185 +/- 158 μl / min; p ≦ 0.02) and contrast sensitivity (+ 34%; 9
2 +/− 11 to 122 +/− 11 log units; p ≦ 0.01) were present 110 +/− 8 minutes after administration of sildenafil. The microcirculation of the retina is 7 out of 9 eyes
Increased in. There was a stable scan here (+ 8%; p ≦ 0.09)
. Perimetric results did not change significantly, nor did mean systolic and diastolic blood pressure, systemic pulse size, and intraocular pressure. None of the subjects reported any subjective visual symptoms (Sponsel et al., 2000).

Pulsatile ocular blood flow results from cardiac synchronized filling of the choroidal circulation. Here, most of the blood volume of the eye is found. The increase in pulsatile choroidal blood flow after administration of sildenafil was probably due to dilation of choroidal blood vessels. Because there was no change in intraocular pressure or systemic pulse size, other major determinants of choroidal blood flow.

The mechanisms associated with the use of sildenafil citrate as a method of treating erectile dysfunction may explain its effective use in the methods of the invention. The physiological mechanism of penile erection is associated with the release of nitric oxide (NO) in the corpus cavernosum of the penis during sexual stimulation. NO then activates the enzyme guanylyl cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), which results in smooth muscle relaxation in the cavernous body of the penis, and blood Inflow. Sildenafil has no direct relaxing effect on isolated human corpus cavernosum, but inhibits type 5 PDE (PDE5), which responds to cGMP collapse in the corpus cavernosum. To enhance the effect of nitric oxide (NO). No sexual stimulation
Inhibiting PDE5 by sildenafil results in increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and blood flow into the corpus cavernosum.

In vitro studies (by Pfizer) show that sildenafil is selective for PDE5. This effect is PDE5 better than other known PDEs.
For PDE6 (> 10 fold, PDE1 80 fold, PDE2, PDE3, and PDE4> 1000 fold). Approximately 4000-fold selectivity for PDE5 over PDE3 is important. Because PD
This is because E3 is involved in the control of cardiac contractility.

3. Formulations for Use in the Treatment of Ocular Disease Conditions Agents for use in the methods of the invention may be delivered orally, systemically, or directly to the eye. It may be formulated for topical application. The use of the term "application" refers herein to any method of delivery. This is oral,
Includes systemic, local, or otherwise. These delivery systems are effective for administering the composition for use in the methods of the invention to the eye for the purpose of increasing the velocity of optic nerve and retinal blood flow. Obviously, according to the invention, the composition may be administered in the form of a solution, gel, semi-solid, suspension, measured dose device, transdermal patch, or film. Other delivery means are also contemplated. The routes of administration of sildenafil citrate are, for example, typically oral and parenteral (including ophthalmic, transdermal, pulmonary circulation, nasal, buccal, sublingual).

Preferred compositions for use in the methods of the invention typically include, but are not necessarily limited to, solutions, gels, semisolids, suspensions, measured dose devices, transdermal patches, or films. Not limited. These include, for example, factors that enhance ocular blood flow, buffer systems (eg, hydrochloric acid, sodium hydroxide, boric acid, sodium borate, acetic acid, sodium acetate, sodium diphosphate, monobasic sodium phosphate, dibasic). Sodium phosphate, sodium carbonate, sodium phosphate (sodium
acid phosphate), disodium phosphate, sodium thiosulfate;
0.1-5% for each), storage system (for example, benzalkonium chloride, 0.01-5%, benztonium chloride, 0.01-5%, chlorobutanol,
0.01-5%, methylparaben, 0.01-5%, propylparaben, 0.0
1, phenylmercuric acetate, 0.01 to 5%, phenylmercuric nitrate, 0.01 to 5%, thimerosal, 0.01, sorbic acid, 0
． 01-5%, sodium perborate, 0.01-5%, benzyl alcohol, 0
． 01-5%), absorption enhancer systems (eg polysorbate 80,0)
． 005-6%, tocopherol TPGS, 0.01-10%, tyloxapol, 0.005-6%, etc.), stabilizer system (eg ascorbic acid, 0.
01-5%, tocopherol, 0.01-5%, disodium ethylenediaminetetraacetate, 0.01-5%, tetrasodium ethylenediaminetetraacetate, 0.01-5
%, Etc., surfactant systems (eg polysorbate 80, 0.005
6%, tyloxapol, 0.005-6%, poloxamer, 0.5-10%, etc.), viscosity increasing system (eg polyvinyl alcohol, 0.5-5%, polyethylene glycol, 0.5-5%, hydroxy). Propylmethyl cellulose, 0.
5-5%, povidone, 0.5-5%, hydroxyethyl cellulose, 0.5-5
%, Methylcellulose, 0.5-5%, dextran, 0.5-5%, acacia, 0.5-5%, white petrolatum, 50-99.9%, mineral oil, 1-8%
, Lanolin, 1-8%, propylene glycol, 1-20%, glycerin, 1-
20%, carbopol, 1-10%, carboxymethylcellulose, 0.5-5
%, Lanolin alcohol, 0.5-5%, etc.), gelling system (eg, carbopol, 1-10%, polyvinyl alcohol, 0.5-5%, hydroxypropyl cellulose, 0.5-10%, hydroxy) Ethyl cellulose, 0.5-10
%, Methylcellulose, 0.5-10%, poloxamer, 0.5-10%, polyacrylamide, 0.5-10%, hyaluronic acid, 0.5-10%, gellan gum, 0.5-10%, pectin , 0.5-10%, etc.), osmotic pressure regulation system (potassium chloride, 0.2-0.9%, sodium chloride, 0.2-0.9%, magnesium chloride, 0.2-0.9%) , Calcium chloride, 0.2-0.9%, zinc sulfate,
0.2-0.9%, polyethylene glycol, 0.2-0.9%, boric acid, 0.
2 to 0.9%), and vehicle (eg water, white petrolatum; 5 each)
.About.99.9%).

Some compositions for use in the present invention may include all of the elements listed above, while other useful compositions include less than all of the elements listed above. May be included. It generally acts to increase stability, shelf life, shelf life, etc. Containing a compound that enhances ocular blood flow (ie, by increasing NO, increasing cyclic-GMP, and / or inhibiting cGMP PDE), eg, with a buffering system and vehicle It may be expected that the composition may be useful. Alternatively, compositions containing compounds that enhance ocular blood flow may be useful, both in systems that increase viscosity and in systems that regulate osmotic pressure. These examples are intended as illustrations of certain preferred embodiments, and are not meant to be exhaustive or limiting as to the scope of the invention in any way.

A preferred composition comprises sildenafil citrate in an oral or ophthalmic preparation, as described above. For those embodiments in which sildenafil citrate is administered orally, sildenafil citrate is typically present in an amount in the range of between about 5 mg and about 500 mg per dose. More preferably, the oral dose is between about 10 mg and about 400 mg sildenafil citrate, or between about 15 mg and about 300 mg sildenafil citrate, or about 20 mg.
To about 250 mg sildenafil citrate, or about 25 mg to about 20
Contains between 0 mg sildenafil citrate. Most preferably, the oral dose comprises between about 50 and about 100 mg sildenafil citrate. For example, about 5 mg
To about 500 mg range from all combined amounts within that range (ie, 6 mg, 7 mg, 8 mg, 9 mg, etc., 30 mg, 31 mg, 32 mg, 33
55mg, such as 45mg, 46mg, 47mg, 48mg, 49mg, etc.
, 56mg, 57mg, 58mg, etc., 75mg, 76mg, 77mg, 78m
101 mg, 102 mg, 103 mg, 104 mg, 150 mg, etc.
151mg, 152mg, 153mg, etc., 201mg, 202mg, 203m
220 mg, 221 mg, 222 mg, 223 mg, etc.
450mg, 451mg, 452mg, 453mg, etc. 475mg, 476m
g, 477 mg, 478 mg, 479 mg, etc.).

Preferred ophthalmic preparations of the present invention generally include, for example, at a concentration of between about 0.001% and about 20% (weight per volume) (including all amounts within that range). ),
Contains sildenafil citrate. More preferably, sildenafil citrate is
Present in the ophthalmic preparation at a concentration of between about 0.01 and 5%, and most preferably, the ophthalmic preparation of the present invention comprises about 1% sildenafil citrate. Of course, one of ordinary skill in the art appreciates that the stated range includes all amounts within that range (ie,
%, 0.03%, 0.04%, etc. 0.1%, 0.11%, 0.12%, etc. 0
． 2%, 0.3%, etc., 1%, 1.1%, 1.2%, 1.3%, 1.4%, etc.
4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4
． 7%, 4.8%, 4.9%, etc., 15%, 16%, 17%, 18%, 19%, etc.).

If desired, a convenient mode for delivering the measured doses is through the use of a device pressurized with a propellant system or by aqueous pump spray. 1,1,1,2-Tetrafluoroethane (30-99.9%) and / or 1,1,1,2,3,3,3 as a propellant system
-Heptafluoropropane (30-99.9%), or other known propellants. When used, ethanol is typically a co-solvent (0.5-5%
Other solvents may also be useful in combination with the method of the present invention. The average droplet size distribution for the preferred propellant-pressurized measured dose inhaler is 2-5 microns, and for the nasal pressurized measured dose inhaler The preferred average droplet size distribution is 10-2.
It is 0 micron.

An exemplary process for formulation is as follows: For solution formulations, factors that enhance blood flow in the blood vessels of the eye (eg sildenafil citrate (3.5 mg / ml soluble)). Is dissolved in a portion of the vehicle. The vehicle includes a co-solvent system to increase the solubility of the drug (a factor that enhances blood flow in the blood vessels of the eye) in the vehicle. The pH of the solution is adjusted and the solution is buffered. The solution is stored and the elasticity is adjusted. The viscosity of the solution is adjusted by adding a factor that increases the viscosity. The final volume of solution is adjusted using the rest of the vehicle. The solution is packaged in a suitable container / closure system to optimize drug stability and end product integrity.

For gel formulations, the gelling agent is dissolved in an aliquot of water.
Drugs, preservatives, stabilizers, buffers, and osmolality adjusting agents are dissolved in separate portions of water. This mixture is mixed with the gel and stirred until homogeneous. The temperature can be raised to accelerate the mixing process. Higher shear capacity homogenizers are preferred for preparing gel formulations. The drug-containing gel is packaged in a suitable container / closure system to optimize drug substance stability and end product integrity.

For semi-solid formulations, the vehicle is heated using a small amount of heat and the preservative is added to the molten vehicle mixture. Then the drug
Incorporated using continuous mixing into a melted vehicle mixture, and 250
Homogenized at 0-5000 psi. The preparation is removed from the heat source,
Then continue mixing at room temperature until set. The final semi-solid is packaged in a suitable container / closure system to optimize drug stability and end product integrity.

For suspension formulations, excessive solubility (eg, 3 of sildenafil citrate
． An amount of micronized agent (5 mg / ml or more) is added to the aqueous vehicle containing the surfactant system, storage system, buffer system, osmolality system, and viscosity enhancing system. The suspension is dispersed using a high shear capacity mixing device (pressure 5000 psi) until the drug is homogeneously dispersed. The final suspension, which contains factors that enhance blood flow in the blood vessels of the eye, has a suitable container / in order to optimize drug substance stability and end product integrity.
Packaged in a closure system.

It is contemplated that the container / closure system containing the composition will be included in a kit with instructions for administration useful for increasing ocular blood flow. The instructions will typically include guidance on dosages, applications, frequencies, and other relevant information for practicing the methods of the invention.

Film formulations (for delivery to the eye, skin, buccal cavity) are prepared by hot melt extrusion, cast film methods, or other methods suitable for forming thin films. A preferred method is to mix a factor that enhances blood flow in the blood vessels of the eye, such as sildenafil citrate, with a mixture of thermoplastic polymers, and hot melt extrusion of the mass containing the drug through a suitable extruder. Is. Film thickness is processed by the ingredients of the formulation and by manipulating the parameters of the extruder. The film containing the drug is cut to the appropriate size for ophthalmic, buccal, or transdermal application, and to optimize drug substance stability and end product integrity And packaged in a suitable container / closure system.

Once again, the application of a film packaged in a container / closure system, as contemplated by the present invention, is effective for increasing blood flow in the eye or for treating macular disorders and the like. Can be included in the kit, along with instructions for. The instructions typically include information such as the location of application of the film, frequency of application, duration of application, and the like. The instructions may be printed on the outside of the container / enclosure system enclosing the film or may be included in the kit separately from the film container / enclosure system.

For a pressurized measured dose inhaler, a factor that enhances blood flow in the blood vessels of the eye (eg, sildenafil citrate) is mixed with ethanol to produce a “drug concentrate”, Aliquots of drug concentrate are then dispensed into epoxy-lined aluminum cans (or lined Type I glass vials).
A measurement (preferably 20-150 microliters) is shaped on the neck of the can. The propellant system is filled up to that value. A small can is combined with the actuator (oral for lungs; nasal for nasal delivery; ophthalmic for ocular delivery). Alternatively, a factor that enhances blood flow in the blood vessels of the eye (eg, sildenafil citrate) is administered in an aqueous dispersion at a dose measured using a pump. The drug is mixed with a surfactant and water. After mixing to dissolve the drug, a viscosity increasing agent is added and the mixture is stirred. The storage system is dispersed and the mixture is agitated. The drug formulation is filled into a container (high density polyethylene) and the pump is screwed on.

The following examples are included to demonstrate preferred embodiments of the invention. It may be discovered by the inventors that the techniques disclosed in the following examples work well for practicing the invention and may therefore be considered to constitute preferred embodiments for practicing the same. Should be apparent to one of ordinary skill in the art. However, one of ordinary skill in the art appreciates that, with reference to the present disclosure, many modifications can be made within the specific embodiments disclosed and still without departing from the spirit and scope of the invention. , It is clear to obtain similar or similar results.

Example 1 A 63-year-old male with extreme central peripheral visual field loss to the right eye and collapsing choroidal optic neuropathy was placed in his right temporary in the Humphrey 30-2 SITA-standard test. A new dilation of the inferiotemporal scotoma developed. In this test, a 14 dB limit was split and fixed in the macular region of the quadrant. Patients underwent a dozen or more prior Humphrey visual field tests. This indicates a permanent progression of visual field loss despite maintaining intraocular pressure (IOP) of 6-10 mmHg without drug administration. The clockwise limit from the nose head to the central periphery was 26, 26, 14, and 25 dB (Fig. 6A).

Immediately after the visual field and contrast sensitivity tests were performed, the patient was given a single oral dose of 50 mg of sildenafil citrate (Viagra®), and 11
These visual tests were repeated after 0 minutes. There was a dramatic loss of visual field loss around the center. This has increased to the limit of 14 to 23 decibels. The marginal values around the center were 28, 29, 23, and 26 dB clockwise, with an average increase of 3.75 decibels for the location of the macular region, a nearly 10-fold increase in light sensitivity. (FIG. 6B).

Central retinal contrast sensitivity measurements performed before and after administration of sildenafil also showed a clear improvement. Wave pattern of 7 degree sine of 1 to 4 cycles per 1 degree (cpd) at 15 inversions per second (NeuroScienti
fic) is shown before and after sildenafil. Three complete sets of training of contrast sensitivity measurements for both eyes were performed prior to testing. 5.8 and 44 respectively
． Lower thresholds of 0 were obtained at 1 and 4 cpd in eyes with loss of visual field (OD) around the center before drug administration. Subsequent eye limits were 10.0 and 92.3, respectively. After 110 minutes of oral sildenafil administration, left eye measurements were clearly constant but visual field loss (OD) around the center.
) Have dramatically increased to 31.2 and 92.3 at 1 and 4 cdp, respectively. IOP and blood pressure were unchanged.

Example 2 Another patient, an agile 78-year-old retired vascular surgery professor, was given pulsatile ocular blood flow measurements and Humphrey 10-2 visual field analysis at 50 mg orally. Of sildenafil before and 1 hour after that. In his more diseased right eye, the entire upper nasal field of view is a complete non-functional scotoma, and even 10 out of 17 of the temporary quadrant positions. It also had a limit value of zero (
FIG. 7A). Note that almost all of the visual functions of the right nose extending from the top of the nose to the macular region are non-functional.

The patient's pulsatile eye blood flow (POBF) in this eye is already quite high, 1
It was 554 μl / min. One hour after taking sildenafil, POB in his right eye
F increased to 1975 μl / min. The quadrant above the nose, which was previously blind,
Here we show successive positions with a visual limit of 26, 28, and 27 decibels, crossing 6 degrees in the upper center of the horizontal meridian, and of 17 of the temporary positions. 16 of them had positive limits here, and 15 of them were double digits (FIG. 17B).

Example 3 As is quite clear, sildenafil citrate still positively affects blood flow and visual function in a very brief period of time when administered orally. Can be given. Similar surprising results were obtained by topical application of drug-containing compositions: to a 45 year old male with normal visual function, slit lamp, and basal findings. , Humphrey 10-2 total limiting central visual field analysis and contrast sensitivity test (1
Wave patterns of 7 degrees sine, 1 to 4 cycles per degree; NeuroScientific) were applied at 15 inversions per second. Subjects underwent multiple prior Humphrey visual field tests and contrast sensitivity tests to rule out any expected significant learning effect on repeated tests.

Immediately after performing the basal visual field and contrast sensitivity tests, he was given a drop of artificial tear solution in a masked fashion in his right eye and 1 in his left eye. Drops of sildenafil solution (sildenafil 1% (Schein buffered to pH 8.0
10 mg / ml)) in the artificial tear solution. He reported no discomfort with any one drop. And he did not know which factor the eye received. He repeated the test of visual function in both eyes 100 minutes after receiving the eye drop.

In the eyes receiving sildenafil, there was a dramatic increase in contrast sensitivity around the core, but the function of sham-treated eyes remained relatively constant. 1
The contrast sensitivity (CS) ratio for one cycle per degree stimulus was 203 in the right eye and 235 in the left eye before treatment. The sham-treated right eye had a CS ratio of 235 after 100 minutes, whereas the eye treated with sildenafil had a CS ratio of 317 (p <0.0001). The increase in CS ratio for 4 cycles per stimulus with sildenafil was similarly striking, and 100 minutes after treatment, 581 of the left eye treated with sildenafil versus the right eye sham treated. Had a value of 194 (p <0.0001).

The Humphrey 10-2 field showed a similar phenomenon. Even though the left eye had a lower photosensitivity than the right eye before treatment, this was significantly higher than the right eye at 100 minutes after receiving topical sildenafil. showed that. The average limit of pretreatment for the 10-degree visual field of the left eye is 31.2 (+ /
-0.19) decibels; 100 minutes after application of the eye drops of sildenafil, this increased to 32.7 (+/- 0.17) decibels (p <0.0001), 70%. Was an increase. Intraocular pressure remained at about 100 mmHg in both eyes and did not rise during the experimental period. There were no adverse effects elicited or significant visual symptoms, and eye appearance, pupil diameter, conjunctival and corneal appearance were symmetrical and normal in both eyes.

Example 4 FIGS. 1A and 1B show scan laser Doppler velocometry.
Figure 3 shows patient data from 3 patients showing an increase in retinal blood flow and blood velocity as measured using a Ning laser doppler velocimetry). This data shows that 50 mg of oral sildenafil citrate (
Viagra®) shows an increase over a period of time up to about 85 minutes. FIG. 1A shows Heidelber for 3 test subjects over time.
g Retinal Flowmetry (HRF) -measured graph of retinal blood flow. FIG. 1B shows Heid for three subjects over time.
FIG. 6 is a graph of retinal blood velocity as measured by elberg Retinal Flowmetry (HRF).

Example 5 FIGS. 2A and 2B show 50 mg of oral sildenafil citrate (Viag).
Figure 2 shows data from two patients showing an increase in contrast sensitivity over a period of time from about 75 minutes to 125 minutes after administration of ra <(R)>. 2A is 2
4 is a graph of 4.26 SF cpd contrast sensitivity (visual and aortic function) over time for a human subject. FIG. 2B shows two test subjects over time,
8 is a graph of 8.53 SF cpd contrast sensitivity (visual function of central macula).

Example 6 FIGS. 3A and 3B show improvements in visual field response for two separate individuals. This report shows both basal (left side of each figure) and after administration of 50 mg oral sildenafil citrate (Viagra®). Figure 3A
Is the Humphrey Frequency Doubling Techno for the basal (left) and post-application (right) status for the first test subject.
Provides a report of the field of view of the logity (FDT). Figure 3B shows the Humphrey F for the basal (left) and post-application (right) status for the second test subject.
It provides a field of view of the Frequency Doubling Technology (FDT).

Example 7 FIGS. 4A, 4B, 5A, and 5B show 50 mg of sildenafil citrate (V
Figure 3 shows patient data from two patients showing other relevant ocular data over a period of time from about 100 to 200 minutes after administration of iagra (R)). FIG. 4A shows pulsatile ocular blood flow (OB) for two test subjects over time.
It is a graph of F). FIG. 4B shows OB for two test subjects over time.
7 is a graph of intraocular pressure measured in association with F. FIG. 5A is a graph of the density of the blue area (retinal capillary circulation volume around the macula) for two test subjects over time. FIG. 5B is a graph of mean velocity in the blue area (retinal capillary circulation around the macula) for two test subjects over time.

Although the present invention has been described with reference to specific embodiments, this description is not intended to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternative embodiments of the invention, will be apparent to persons skilled in the art upon reference to the description of the invention.

REFERENCES The following references are specifically incorporated herein by reference to the extent that they provide the exemplary procedures provided herein or other ancillary details. To be done.

[0083]

[Equation 1] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The present invention may be better understood with reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

[Brief description of drawings]

FIG. 1A shows Heidelberg R for three test subjects over time.
Fig. 3 is a graph of blood flow in the retina measured by etinal Flowmetry (HRF).

FIG. 1B shows Heidelberg R for three test subjects over time.
FIG. 6 is a graph of retinal blood velocity as measured by etinal Flowmetry (HRF).

FIG. 2A is a graph of 4.26 SF cpd contrast sensitivity (visual function) for two test subjects over time.

FIG. 2B is a graph of 8.53 SF cpd contrast sensitivity (central macular visual function) for two test subjects over time.

FIG. 3A is a Humphrey Frequency Doubling Technology for the basal (left) and post-application (right) status of the first test subject.
Provides a logistic (FDT) visual field report.

FIG. 3B is a Humphrey Frequency Doubling Te for basal (left) and post-application (right) status for a second test subject.
A field of view report of chnology (FDT) is provided.

FIG. 4A shows pulsatile ocular blood flow (OB) for two test subjects over time.
It is a graph of F).

FIG. 4B is a graph of OBF-associated measured intraocular pressure for two test subjects over time.

FIG. 5A is a graph of the density of the blue area (retinal capillary circulating volume around the macula) for two test subjects over time.

FIG. 5B shows the average velocity (blue area) of two test subjects over time (
Fig. 7 is a graph of the circulation velocity of capillaries in the retina around the macula).

FIG. 6A is a Humphrey visual field test, which was performed without drug administration.
Shows the extent of progression of permanent visual field loss despite maintaining intraocular pressure (IOP) up to -10 mmHg. From the top of the nose to the right, the limit around the center is
26, 26, 14, and 25 dB.

FIG. 6B: The clockwise progression of threshold values around the center is 28, 29, 23, and 26 dB, with an average increase of 3.75 decibels for the location of the macular region, almost a 10-fold increase in light sensitivity. It was an increase.

FIG. 7A shows that before and 1 hour after ingestion of sildenafil 50 mg orally,
Humphrey 10-2 visual field test.

FIG. 7B is a Humphrey visual field test, which is 26, 28, and 2.
A visual limit of 7 decibels passes through the central 6 degrees on the horizontal meridian, and 1
The upper temporal location of 16 of 7 has a positive limit here, indicating that 15 of them were double digits.

[Procedure amendment]

[Submission date] March 15, 2002 (2002.15)

[Procedure Amendment 1]

[Document name to be corrected] Drawing

[Name of item to be corrected] Fig. 6A

[Correction method] Change

[Contents of correction]

FIG. 6A

[Procedure Amendment 2]

[Document name to be corrected] Drawing

[Correction target item name] Fig. 6B

[Correction method] Change

[Contents of correction]

FIG. 6B

[Procedure 3]

[Document name to be corrected] Drawing

[Correction target item name] Figure 7A

[Correction method] Change

[Contents of correction]

FIG. 7A

[Procedure amendment 4]

[Document name to be corrected] Drawing

[Name of item to be corrected] Fig. 7B

[Correction method] Change

[Contents of correction]

FIG. 7B

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Claims (10)

[Claims] 1. An ophthalmically acceptable carrier and ocular cyclic-GM.
For use in increasing ocular blood flow, comprising a factor that increases cyclic-GMP in an amount effective to increase the level of P, thereby increasing ocular blood flow, Ophthalmic preparation. 2. The cyclic-G, wherein the factor is selective for cyclic-GMP phosphodiesterase inhibitor, type 5 phosphodiesterase.
An ophthalmic preparation according to claim 1, which is an MP phosphodiesterase inhibitor, a guanylyl cyclase activator, or a cyclic-GMP analog. 3. The factor is sildenafil citrate, dipyridamole, zaprinast, filaminast, denbuphylene, piclamilast, zardaverine, carboline derivative, pyridocarbazole derivative, quinazolinone compound, sodium azide, sodium nitrate, hydroxylamine, hydrazine, nitroglycerin. The ophthalmic preparation of claim 2, selected from the group consisting of :, nitroprusside, nitrosoureas, and nitrosamines. 4. Use of a factor that increases cyclic-GMP levels in the manufacture of a medicament for preventing or treating an ocular disorder by increasing blood flow in the eye of a patient. 5. The cyclic-G, wherein said factor is selective for cyclic-GMP phosphodiesterase inhibitor, type 5 phosphodiesterase.
Use according to claim 4, which is an MP phosphodiesterase inhibitor, a guanylyl cyclase activator, or a cyclic-GMP analog. 6. The factor is sildenafil citrate, dipyridamole, zaprinast, filaminast, denbuphylene, piclamilast, zardaverine, carboline derivative, pyridocarbazole derivative, quinazolinone compound, sodium azide, sodium nitrate, hydroxylamine, hydrazine, nitroglycerin. Use according to claim 5, selected from the group consisting of :, nitroprusside, nitrosoureas, and nitrosamines. 7. Use according to any one of claims 4 to 6, wherein the medicament is intended to prevent or treat an eye disorder selected from the group consisting of: optic nerve disease, Normotensive depression optic neuropathy, ischemic optic neuropathy, toxic optic neuropathy, traumatic optic neuropathy, idiopathic optic neuropathy, optic nerve drus, benign intracranial hypertension, retinal disease, retinal neovascularization Formation, ischemic blood / flow disorders, toxic macular disease, choroidal disease, degenerative subretinal neovascularization, diabetic choroidal ischemia, inflammatory subretinal neovascularization, age-related Choroid ischemia, posterior choroid ischemic injury, macular degenerative drusen, macular retinal pigment epithelium atrophy, retinal pigment epithelium detachment, degenerative subretinal neovascularization, wet age Associated macular regression, macular disorder, macular regression, familial Drusen, macular disorders associated with hypertension, hemangiomas, papillitis, optic nerve retinitis, pigmented retinal degenerative disorders, macular edema without vascular leakage, retinitis pigmentation, pigmented retina Degenerative disorders, early stage macular pores, choroidal neovascularization, macular edema with leaky blood vessels, diabetic retinopathy, branch retinal vein occlusion, intermediate uveitis, idiopathic retina Telangiectasia, and lipofuscin accumulation in the eye. 8. The use according to any one of claims 4 to 7, wherein the medicament is administered parenterally or orally to the patient. 9. The pharmaceutical agent is administered to the eye of the patient.
Use according to any one of 1 to 7. 10. The pharmaceutical agent is administered to the patient as a solution, gel, semi-solid, suspension, metered dose device, transdermal patch, film, or ophthalmic preparation. Use according to any one of claims 4-9.