Note: Descriptions are shown in the official language in which they were submitted.
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DESCRIPTION
METHOD FOR INCREASING OPTIC NERVE, CHOROIDAL AND RETINAL
BLOOD FLOW TO FACILITATE THE PRESERVATION OF SIGHT
BACKGROUND OF THE INVENTION
The present application claims priority to provisional application serial
number
60/148,150 filed August 10, 1999. The entire text of the above-referenced
disclosure is
specifically incorporated by reference herein without disclaimer.
1. Field of the Invention
The present invention relates generally to the field of ocular medicine. More
particularly, it concerns methods for treating ocular disorders and for
maintaining ocular
health. The present invention relates more specifically to a method for
improving visual
function and optimizing the health of the optic nerve and retina by increasing
blood flow
therein through the application of an effective amount of a composition
including an
agent that increases cyclic-guanosine monophosphate (cyclic-GMP) levels,
either
directly, or by stimulating cyclic-GMP synthesis, or by inhibiting cyclic-GMP
selective
phosphodiesterase(s).
2. Background Information
The vision process in general involves a complex pathway into the brain. To
see,
light must enter through the cornea and the lens; penetrate the back of the
eye through the
retina; pass the ganglion cells and bipolar cells; then pass down to the outer
plexiform
layers through the synaptic vesicle, the inner fiber, the nucleus, the outer
fibers, the
terminal bars, the cilium; and finally reach the photoreceptors, which can be
considered
to carry out the instant film processing of the visual light beam. After the
light beam has
been processed in the photoreceptor disks, it passes back through the cilium,
the
ellipsoid, myoid, Mueller cells, outer fiber, nucleus, inner fiber, synaptic
vesicle, the
outer plexiform layer, inner nuclear layer, the bipolar cells, the inner
plexiform layer,
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finally reaching the ganglion cells where it is processed into an axon signal.
After it
reaches the ganglion cells, the signal is transported through the optic nerve
fibers to the
brain where it is assessed and compounded by the visual brain lobes to form
the visual
picture. It is believed that the uninterrupted signal carried by the retina,
the optic nerve
head, and the optic nerve fibers is the most crucial part of the process for
creating the
visual picture. Adequate blood flow nurtures the tissues along this path and,
therefore,
assures axonal flow.
It is understood that the human eye (and indeed the eye structure of most
mammals) has two largely independent circulatory systems, retinal and uveal.
Retinal
circulation accounts for only about 2% of total eye circulation, but this 2%
is critical to
the health of the eye's neural connection to the brain, i.e., the 1.2 million
axons which
make up the nerve trunk known as the optic nerve. The cell bodies containing
the genetic
material and metabolic machinery for this connection are all located in the
inner layer of
1 S the retina, and derive virtually all of their blood supply (i. e.,
including energy,
oxygen/carbon dioxide, and metabolic by-product exchange) from the locally
auto-
regulated retinal circulation. Any significant compromise to the retinal
circulation is
typically accompanied by visual loss.
The vast majority of the eye's inner circulation, on the other hand, passes
through
the uveal system, a sponge-like, erectile tangle of vessels that lies behind
the retina and
its pigment epithelium. This vascular bed provides a rich supply of nutrients
to the
metabolically active photoreceptors of the outer retina, and the pigment
epithelium which
supports them. Moreover, this seemingly excessive blood supply acts as a heat
sink to
absorb thermal energy from focused light which could otherwise damage neural
tissues.
The choroidal circulation, the part of the uveal vascular bed lying directly
behind the
retina, has some local regulation characteristics, but is also supplied with
autonomic
nerves capable of producing major changes in circulatory volume in response to
stimuli,
not necessarily generated in the eye itself.
To address retinal and optic nerve blood flow velocity, it is important to
understand that the retina is essentially a specialized part of the brain, and
its circulation
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is very tightly regulated. Blood flow through the brain is typically constant
in healthy
individuals, whether running a marathon or sleeping. Obviously, huge
variations in the
inflow pressure of carotid artery blood to the brain occur throughout a
typical day, and
the vasculature in the cerebral cortex responds by adjusting its resistance.
This is
accomplished by constriction or dilation of the vessels throughout the brain.
If the
cerebrospinal fluid pressure is increased, creating, in effect, a stiffer
vascular bed in the
cerebral cortex, the blood vessels in the brain dilate to reduce intrinsic
resistance,
maintaining constant blood flow. This process is called autoregulation.
Autoregulation in the retina is analogous to that found in the brain, so if
intraocular pressure is reduced, circulation in the retina is not necessarily
increased. This
point is clearly illustrated as a coincidental feature of the examples of
hyperventilation (to
blow off carbon dioxide and thereby reduce circulation to all the intrinsic
vessels of the
eye) and treatment with latanoprost (increasing the flow of clear fluid out of
the eye),
which both produce significant reduction of intraocular pressure, but with
which visual
function may actually be simultaneously diminished.
Circulation in the retina also is highly pH-dependent. Studies in which
various
gases are introduced via the respiratory system into the blood stream clearly
demonstrate
that as the COZ level increases and pH decreases, circulation to the retina
typically
increases by upward of 40% from the baseline level observed during breathing
of
atmospheric air. Conversely, breathing pure oxygen produces a profound
decrease in
circulation in the retina. This latter response may be in part responsible for
the disease
process known as retrolental fibroplasia, or retinopathy of prematurity, which
causes total
or partial blindness in many premature infants.
In healthy eyes, because of the choroid's relative abundance of vessels,
fairly
large changes in choroidal blood flow may be accompanied by minimal visual
function
change. However, because the uveal circulation comprises a significant portion
of the
ocular volume, a substantial drop in choroidal blood flow is generally
accompanied by a
significant decrease in intraocular pressure. Thus, during hyperventilation
for example,
when the natural vasodilator carbon dioxide is blown off, both choroidal and
retinal
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circulation decrease in tandem, and visual function diminishes
correspondingly.
Typically, an individual with a large intraocular pressure decrease consequent
to
hyperventilation would have a very large visual function deficit.
It has, therefore, become increasingly apparent that blood flow in the retina
and
about the optic nerve plays a critical role in a number of ocular disorders.
New
technologies have facilitated a more thorough examination of the posterior
aspect of the
eye and the evaluation of circulatory, metabolic, and hematologic factors,
thereby being
better able to determine the causes of various eye diseases. In turn, various
therapeutic
agents may be applied to more precisely address the pathophysiology underlying
specific
ocular disorders, more particularly, those ocular disorders whose progression
may be
attenuated, ameliorated, or reversed by improving ocular circulation.
For example, others have used drugs to stimulate cyclic 3', 5'-adenosine
monophosphate (CAMP) production, thereby decreasing intraocular pressure and
increasing ocular circulation. It is well known that beta-adrenergic impulses
in several
tissues are mediated intracellularly by a second messenger, cAMP. cAMP is
produced
from ATP by a membrane bound enzyme, adenylate cyclase. cAMP is believed
further to
activate steps in a chain of processes leading to protein phosphorylation and
final
biologic activity. Generally, it is thought that the cAMP step is a process of
short
duration because CAMP is rapidly and efficiently degraded intracellularly by
CAMP
phosphodiesterases, which are present in abundance.
The pathway by which cAMP is produced is quite complex. cAMP is produced
when adenylate cyclase is activated through the activation of many receptors.
This
stimulation is mediated by GS and by inhibition of at least one other protein
belonging to
the G; class of G proteins. It is known that there are at least ten tissue-
specific adenylate
cyclase isozymes, each having a unique pattern of regulatory responses. Some
of these
isozymes are inhibited by G protein (3y subunits, others are stimulated by
these subunits if
concurrently stimulated by the a subunit of GS, others are stimulated by Ca2+
or Ca2+-
calmodulin complexes. Adrenergic drugs mediate the production of cAMP, thereby
decreasing intraocular pressure and increasing vascular blood flow.
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In general, diseases which may be amenable to treatment with agents capable of
modulating ocular blood flow include, but are not limited to, optic nerve
disease, retinal
disease or choroidal disease. More specific disorders include, but are not
limited to,
5 macular edema or macular degeneration. Macular edema, for example, is
defined as
swelling within the retina in the critically important central visual zone at
the posterior
pole of the eye. An accumulation of fluid tends to distract the retinal neural
elements
from one another and from their local blood supply, creating a dormancy of
visual
function in the area. Usually, the process is self limiting, but occasional
permanent
visual disability results from macular edema. Often times, the swelling may
take many
months to clear. The precise mechanism by which swelling is triggered is
uncertain, but
it is probable that certain natural metabolic toxins may play an important
role in the
disease process. Macular swelling also may follow the insertion of artificial
lens
implants and cataract surgery, particularly if there is a breach in the lens
capsule which
segregates the vitreous gel from the fluid-filled anterior chamber.
Longstanding macular
edema after cataract surgery is one of the most frustrating dilemmas in all of
ophthalmology, and is remarkably common. Macular edema is a common and
alarming
ocular problem, for which no useful form of ocular therapy has been previously
known.
Two types of cystoid macular edema are: (a) those without vascular leakage:
retinitis
pigmentosa and other pigmentary retinal degenerative disorders, early stage
macular hole,
and choroidal neovascularization; and (b) those with vascular leakage:
diabetic
retinopathy; branch retinal vein occlusion; intermediate uveitis; and
ideopathic retinal
telangiectasis.
Another even more common chronic condition is macular degeneration. Instead
of fluid accumulating in the outer retina, hard accumulations of lipofuscin, a
metabolic
waste product, tend to accumulate between the photoreceptors and the villi of
the retinal
pigment epithelium. These accumulations gradually enlarge, and in their early
pathologic
phase create discrete accumulations known as drusen. The lipofuscin is
believed to
accumulate as a result of the breaking off of the photoreceptor elements.
Shedding of the
cellular components of the photoreceptors is constantly occurring in a healthy
retina.
Good retinal pigment epithelial metabolism generally ensures a rapid clearance
of such
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catabolic by-products of vision. The accumulation of this waste material
retards the
interaction between the retina and the retinal pigment epithelium from which
nutrients
arrive and through which catabolites are cleansed, establishing a self
perpetuating cycle
of catabolite accumulation. The accumulations not only block metabolic
transfer
between the retina and retinal pigment epithelium, they actually continue to
undergo
photoresponsive metabolism, constantly wasting precious NADH reducing power
with
no benefit.
Improved local circulation might retard or prevent the accumulation of
lipofuscin
and break the cycle of progressive blockage and waste of metabolic products
passing to
and from the retina. As drusen accumulate in number and begin to coalesce,
vast areas of
retinal photoreceptors may become permanently disengaged from their
neighboring
retinal pigment epithelial villi. The sections of retina so affected become
blind.
Unfortunately, the greatest propensity among the aging population is for
drusen to
accumulate in the very central area of vision, the macula. Thus, macular
degeneration is
the most common cause of legal blindness in the United States and Europe.
Whereas
macular edema generally affects only one eye, macular degeneration typically
involves
both eyes and is usually fairly symmetric in its presentation and progression.
The
problem is on the rise, and is expected to continue to mount.
Obviously, normal metabolism tends to produce catabolic waste with
accumulation of protons and COZ. Many chronic diseases of the ocular tissues
tend to
stagnate local metabolism and the normal catabolites which would otherwise
'recruit'
increased local circulation, are actually not produced. Instead, tissue
breakdown products
accumulate producing a vicious cycle of degredation without replenishment.
Thus, a
variety of agents capable of enhancing local circulation in this situation
could help clear
tissue breakdown products and stimulate a restoration of normal metabolic
function.
SUMMARY OF THE INVENTION
The present invention provides a method for treating an optic nerve disease by
increasing ocular blood flow, perfusion and/or circulation. Ocular blood flow
is
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generally improved by applying a pharmacologically effective amount of an
agent that
enhances ocular vascular blood flow either directly to the eye or
systemically. As used
herein, the phrase "agent that enhances ocular vascular blood flow" refers to
cyclic-GMP
analogs, agents that inhibit cyclic-GMP phosphodiesterase(s) (PDE), agents
that increase
the activity of guanylate cyclase, agents that increase levels of cyclic-GMP,
or agents that
increase levels of nitric oxide (NO) in the tissues of the eye. For example,
agents that
either enhance the production or increase the availability or longevity of NO,
thereby
activating guanylate cyclase, would increase levels of cyclic-GMP and cause an
increase
in ocular blood flow.
In preferred embodiments, the optic nerve disease to be treated includes but
are
not limited to normotensive excavatory optic neuropathy, ischemic optic
neuropathy,
toxic optic neuropathy, traumatic optic neuropathy, or idiopathic optic
neuropathy.
Examples of normotensive excavatory optic neuropathy include primary optic
atrophy,
ocular ischemic syndrome, shock-associated optic 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 neuroretinitis. Examples of idiopathic optic
neuropathy include optic nerve drusen or benign intracranial hypertension. In
certain
aspects of the present invention, multiple optical nerve diseases occurring in
the same
patient are treated using the compositions and methods of the invention.
Alternatively, the invention provides methods for treating retinal disease by
administering a composition comprising an agent that enhances ocular vascular
blood
flow to a patient suffering from a retinal disease or applying the composition
directly to
the affected eye. In certain aspects, the retinal disease to be treated may be
retinal
neovascularization, ischemic hematologic/rheologic disorders or toxic
maculopathy.
Examples of retinal neovascularization include a diabetes related form of
retinal
neovascularization, hemoglobinopathy or inflammatory vascular narrowing. The
diabetes related form of retinal neovascularization is may be, for example,
diabetic
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macular edema, ischemia and neovascularization or non-proliferative diabetic
retinopathy. An example of hemoglobinopahy is sickle cell trait. Examples of
inflammatory vascular narrowing include lupus, collagen vascular diseases, HIV
retinopathy, CMV retinopathy or sarcoidosis. Examples of ischemic hemotologic/
rheologic disorder include central retinal vein occlusion or branch retinal
vein occlusion.
Examples of toxic maculopathy include drug related maculopathy or chloroquine
retinopathy. In certain aspects of the present invention, multiple retinal
diseases
occurring in the same patient are treated using the compositions and methods
of the
invention.
In certain other preferred methods of the invention, choroidal disease is
treated by
applying a therapeutically effective amount of a composition comprising at
least a first
agent that increases ocular blood flow to an affected eye. Examples of
choroidal disease
include, but are not limited to, an ischemic disorder of the posterior
choroid, degenerative
subretinal neovascularization, diabetic choroidal ischemia, inflammatory
subretinal
neovascularization, or non-age related choroidal ischemia. Examples of
ischemic
disorder of the posterior choroid include degenerative drusen of the macula
(i. e. dry age
related macular degeneration), macular retinal pigment epithelial atrophy, and
retinal
pigment epithelial detachment. An example of degenerative subretinal
neovascularization is wet age related macular degeneration. Examples of
diabetic
choroidal ischemia include diabetic choroidopathy. Examples of inflammatory
subretinal
neovascularization include presumed ocular histoplasmosis syndrome. Examples
of non-
age related choroidal ischemia include myopic degeneration or high myopia. In
certain
aspects of the present invention, multiple choroidal diseases occurring in the
same patient
are treated using the compositions and methods of the invention.
Of course, patients often present with multiple forms of any of the above
diseases
and the compositions and methods described herein are effective for treatment
of
multiple disorders in the same patient. For example, the compositions and
methods
described herein are useful for treating a patient suffering from an optical
nerve disease
and a retinal disease.
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The methods of the invention are further effective for the treatment of
macular
disorders such as macular edema, macular degeneration, drusen, macular
disorders
related to hypertension, angioma, papillitis, neuroretinitis or pigmentary
retinal
degenerative disorders, toxic maculopathy and maculopathy secondary to
rheologic
abnormalities. The methods of the invention are useful for treatment of
macular edema
with or without vascular leakage. Examples of macular edema without vascular
leakage
include retinitis pigmentosa, pigmentary retinal degenerative disorder, early
stage
macular hole, or choroidal neovascularization. Examples of macular edema with
vascular leakage include diabetic retinopathy, branch retinal vein occlusion,
intermediate
uveitis or ideopathic retinal telangiectasis. The methods of the invention may
also be
used to inhibit or prevent the accumulation of lipofuscin in an eye.
In the methods of the invention described above, the agent to be included in
the
composition is a cyclic-GMP analog, a compound that inhibits cyclic-GMP
PDE(s), a
compound that activates guanylate cyclase, or a compound that increases levels
of cyclic-
GMP. Preferred cyclic-GMP analogs include 8-bromoguanosine-3,5-cyclic
monophosphate. Preferred agents that inhibit cyclic-GMP PDE(s) include
sildenafil
citrate, dipyridamole, zaprinast, filaminast, denbufyllene, piclamilast, or
zardaverine,
carboline derivatives, pyridocarbazole derivatives, or quinozolinone
compounds. In
certain preferred aspects, the PDE inhibitor is selective for PDE type 5
(PDES) or PDE
type 6 (PDE6). Preferred agents that activate guanylate cyclase (by increasing
levels of
NO) include sodium azide, sodium nitrite, hydroxylamine, hydrazines,
nitroglycerine,
nitroprusside, nitrosureas or nitrosamines. By activating guanylate cyclase,
these agents
also increase levels of cyclic-GMP. NO levels may also be increased by NO
donors or
NO synthase stimulators and such compounds are useful in the compositions for
use in
the methods of the invention. Preferred NO donors include sodium
nitroprusside,
nitroglycerine, SIN-1, isosorbide mononitrate, isosorbide dinitrate,
diethylenetriamine/NO, glycerol trinitrite, pentaerytrityl tetranitrite,
mannitol hexanitrite,
inositol hexanitrite or propatyl nitrate. Preferred NO synthase stimulators
include 2-aryl-
(3-thiophens. Other preferred compounds include nitrosated and/or nitroxylated
PDE
inhibitors or polymeric material that releases NO. Combinations of two or more
of the
agents listed above are also contemplated in certain aspects of the present
invention.
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Preferred methods of application include oral and parenteral (including
ophthalmic, transdermal, pulmonary, nasal, buccal or sublingual). More
specifically, the
compositions may be administered by way of a solution, gel, semisolid,
suspension,
5 metered dose device, transdermal patch or film.
Another aspect of the invention provides a kit for treatment of ocular
disorders
including a sealed container housing a composition comprising an agent that
increases
ocular vascular blood flow and instructions for administering the composition
to a patient
10 suffering from an ocular disorder such that the patient's ocular blood flow
is increased.
The compositions included in the kit of the invention include agents as
described above.
The present invention also provides an effective treatment for maintaining the
health of the eye and effectively treating various other ocular conditions by
improving
ocular blood flow in the retina and choroid of the eye and in and about the
optical nerve.
In addition to the indications above, the present invention contemplates
administration of the compositions described herein to subjects with normal
vision for
the purpose of increasing visual function including but not limited to visual
acuity,
contrast sensitivity and perimetric light sensitivity.
BRIEF DESCRIPTION OF THE DRAWINGS
The following drawings form part of the present specification and are included
to
further demonstrate certain aspects of the present invention. The invention
may be better
understood by reference to one or more of these drawings in combination with
the
detailed description of specific embodiments presented herein.
FIG. 1A is a graph of retinal blood flow as measured by Heidelberg Retinal
Flowmetry (HRF) for three test subjects over time.
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FIG. 1B is a graph of retinal blood velocity as measured by Heidelberg
Retinal Flowmetry (HRF) for three test subjects over time.
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 provides Humphrey Frequency Doubling Technology (FDT) visual
field reports for a first test subject baseline (left) and post-application
(right) conditions.
FIG. 3B provides Humphrey Frequency Doubling Technology (FDT) visual
field reports for a second test subject baseline (left) and post-application
(right)
conditions.
FIG. 4A is a graph of pulsatile ocular blood flow (OBF) for two test
subjects over time.
FIG. 4B is a graph of intraocular pressure measured concomitantly with
OBF for two test subjects over time.
FIG. 5A is a graph of blue field density (perimacular retinal capillary
circulatory volume) for two test subjects over time.
FIG. 5B is a graph of blue field mean velocity (perimacular retinal capillary
circulatory speed) for two test subjects over time.
FIG. 6A Humphrey visual field tests, showing extent of the perpetual
progression of field loss despite maintaining intraocular pressures (IOP) from
6-10
mmHg without medication. Pericentral thresholds clockwise from superionasal
were 26,
26, 14, and 25 dB.
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FIG. 6B Clockwise progression of pericentral threshold values was 28, 29,
23, and 26 dB, a mean increase of 3.75 decibels for the macular region loci,
nearly a
tenfold increase in light sensitivity.
FIG. 7A Humphrey 10-2 visual field test, prior to and one hour after
ingestion of 50 mg oral sildenafil.
FIG. 7B Humphrey visual field test showing visual thresholds of 26, 28,
and 27 decibels across the central six degrees above the horizontal meridian,
and 16 of
the 17 superotemporal loci now had positive thresholds, 15 of which were in
double-
digits.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
1. Enhanced Blood flow For Treatment of Ocular Disorders
Surprisingly, agents that enhance blood flow to and around the optic nerve
have
been found to be useful in treating a number of eye disorders. It is known
that relatively
large changes in choroidal blood flow may be accompanied by minimal visual
function
change. However, retinal circulation is very tightly regulated within the
brain. The
majority of the eye's inner circulation passes through the uveal system, lying
behind the
retina and its pigment epithelium. Choroidal circulation is part of the
vascular bed lying
directly behind the retina and contains autonomic nerves capable of producing
major
changes in circulatory volume in response to stimuli, which may be generated
within the
eye or outside of the eye.
While the vision process is quite complex, it is believed that the signal
carried by
the retina, the optic nerve head, and the optic nerve fibers is the most
crucial part of the
process. Adequate blood flow nurtures the tissue along this path and assures
transport of
the signal. Many ocular disorders are known to involve some kind of blockage
of or
hindrance to optic blood flow.
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The human choroid, which supports the metabolic function of the outer retina,
is
an erectile tissue, analogous in certain respects to the corpus cavernosum.
The
fenestrated choroidal vasculature is highly responsive to both local and
neurogenic
stimuli, and the uveal system of which it is part may hold up to 98% of the
intraocular
blood volume. Choroidal blood flow has recently been reported to be decreased
in
macular degeneration, the leading cause of acquired blindness in North
America. The
inventor reasoned that agents capable of modulating ocular blood flow would be
of
therapeutic value in the treatment of a range of choroidal, retinal, and
axonal disorders,
provided circulatory augmentation can be achieved without debilitating
metabolic
compromise or vascular leakage.
There are a number of ocular disease states in which increasing ocular blood
flow
is beneficial. The methods of the invention include administering agents that
increase
ocular blood flow to a patient suffering from such an ocular disease state.
Table 1 sets
forth a number of the disease states that would benefit from treatment using
the methods
of the present invention.
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z z ' O y,~~r~ N U C b C N~ ~
~ ~' 7 Q ~
=
~ ~ H ~ .~~ ~ o . z
,
.r ~. o
O rx U
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As illustrated in Table 1 (not intended to be exhaustive), there are generally
three
broad categories of optic disease states for which increased ocular blood flow
is
beneficial. Those are optic nerve disease, retina disease and choroidal
disease. Within
5 those general categories are a number of additional categories with more
specific
examples provided for illustration. Of course, those skilled in the art would
understand
that other disease states in which ocular blood flow is a factor would benefit
from
treatment using the methods of the invention. The benefits of the present
invention are
described in more detail below using a specific type of choroidal disease, age
related
10 macular degeneration, for illustration purposes only. It will be understood
that the
present methods and compositions are useful for the treatment of any optic
disease state.
Age-related macular degeneration (ARMD) is the leading cause of visual loss
among Americans over 60 years of age. As the macula degenerates, central
reading
15 vision deteriorates 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 accounts
for a
high proportion of the most severe visual destruction encountered among ARMD
patients. Wet ARMD, however, only accounts for 10% of ARMD cases. Because of
its
dramatic pathologic course, wet ARMD has received much attention, and numerous
treatment modalities have been devised to abate this form of the disease, most
of which
are directed toward destroying the invading, leaky blood vessels by laser or
other means.
Dry ARMD is far more prevalent, progresses more slowly, and accounts for 90%
of
ARMD cases. Advanced cases of dry ARMD constitute a high proportion of
individuals
declared legally blind in the United States, Europe, Australia, and parts of
Asia. In
addition, a high proportion of wet ARMD cases begin as dry ARMD. Despite the
long-
felt need for effective treatments for dry ARMD, none were available prior to
the present
invention.
The circulation of blood through vessels underlying the retina, in the
choroid, is
compromised in patients afflicted with ARMD (Pauleikboff et al. 1990; Chen et
al.
1990; Giovannini et al. 1994; Grunwald et al. 1994; Friedman et al. 1995; Ross
et al.
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1998; Ciulla et al. 1999; Dontsov et al. 1999). Because the choroid provides
the only
source of nourishment for the photoreceptors in the outer retina, and the only
means for
removing waste products, this decrease in circulation can have dire effects on
the macula,
one of the body's most metabolically active tissues.
In ARMD, accumulation of lipofuscin, an aggregate of breakdown products from
the outer retina. occurs in the interspace between the retinal photoreceptors
and the
villiform pigment epithelial cells with which they interdigitate. The retinal
pigment
epithelium (RPE) is a vital metabolic factory, which reprocesses photopigment
and
carries out many critical support and transport processes, maintaining retinal
function.
The outermost layer of the anatomic sandwich supporting retinal function is
the choroid,
a highly vascular tissue which supplies nutrients to and which clears
catabolites from this
highly active tissue complex. Lipofuscin builds up in the interface between
the RPE and
choroid in diseased eyes. Incompletely-degraded, lipofuscin-bound pigmentary
debris
which accumulates in this space in ARMD constantly seizes and oxidatively
wastes
molecular energy passing from the choroid to the RPE, even in the absence of
light
(Sponsel et al. 2000). Therefore, ARMD, once established, tends to follow a
vicious
pathologic spiral, selectively afflicting the zone of highest metabolic
activity, the macula.
Other major sources of blindness, wet ARMD, myopic degeneration, or diabetic
retinopathy, are characterized by the formation of abnormal vessels behind or
within the
substance of the retina. The new, abnormal vessels which typify these
conditions
proliferate through the action of locally-released hormonal agents, which are
released in
response to attenuated circulation within the eye. Such vessels, even after
they form, are
only sustained by persisting circulatory inadequacy in the surrounding tissue.
Normalization of the balance between metabolic tissue demand, nutrient
provision, and
catabolite clearance results in the regression of these leaky and potentially
blinding
anomalous vessels. Therefore, the present methods and compositions that
increase blood
flow in the retina and choroid are expected to be of benefit in treating the
latter stages of
wet ARMD and proliferative diabetic retinopathy. In addition, timely treatment
of at-risk
individuals with preproliferative diabetes and dry ARMD, as described herein,
is
expected to prevent progression to the neovascular stages of these diseases.
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2. Agents That Enhance Blood flow
The present invention is grounded on the discovery that increasing ocular
blood
flow, particularly in the retina of the eye is a safe and effective way to
maintain the health
of the eye and to treat various ocular disorders that have in their etiology
inadequate
vascular blood flow, such as macular edema and macular degeneration. While the
precise theory is not completely understood, improved (i.e., increased) blood
flow in and
to the retina and choroid of the eye can greatly improve retinal and optic
nerve health
which, in turn, effectively combats 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. When guanylate cyclase is
activated,
cyclic-GMP levels increase. Murad et al. used nitrogen containing compounds,
such as
sodium azide, sodium nitrite and hydroxylamine, to activate guanylate cyclase
and
discovered that these compounds are converted to an active intermediate,
nitric oxide
(NO), that is directly involved in the activation of guanylate cyclase and the
subsequent
conversion of GTP to cyclic-GMP. Thus, agents that activate guanylate cyclase
through
the formation of the intermediate NO, thereby increasing NO levels and,
subsequently,
increasing cyclic-GMP levels, and increasing ocular vascular blood flow, are
particularly
useful in the methods of the present invention. The compositions of the
invention may
include more than one agent that activates guanylate cyclase.
As mentioned above, cyclic-AMP is also known to increase vascular blood flow,
however, it operates through a significantly different pathway than that of
cyclic-GMP.
In short, certain adrenergic drugs mediate the production of cyclic-AMP,
thereby
decreasing intraocular pressure and increasing vascular blood flow. Therefore,
this
mechanism of action is significantly different from the pathway followed by
cyclic-GMP
in the stimulation of ocular vascular blood flow as described herein.
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Besides the agents that activate guanylate cyclase, such as sodium azide,
sodium
nitrite, or hydroxylamine, discussed above, other agents that activate
guanylate cyclase,
increase NO levels and/or increase cyclic-GMP levels also would increase
ocular blood
flow and improve vision. Other guanylate cyclase activators include
hydrazines,
nitroglycerine, nitroprusside, nitrosureas and nitrosamines.
Agents that increase NO levels include those agents that are nitric oxide
donors,
stimulate nitric oxide synthase or increase availability or longevity of
nitric oxide.
Agents that stimulate nitric oxide synthase include 2-aryl-(3-thiophens,
described for
example, in U.S. Patent No. 5,811,437, incorporated herein by reference or
other
compounds described, for example, in U.S. Patent No. x,478,946, incorporated
herein by
reference. Agents that are nitric oxide donors include sodium nitroprusside,
nitroglycerine, SIN-1, isosorbide mononitrate, isosorbide dinitrate,
diethylenetriamine/NO, glycerol trinitrite, petnaerytrityl tetranitrite,
mannitol hexanitrite,
inositol hexanitrite, or propatyl nitrate. Other compounds useful in the
compositions of
the invention include nitrosated and/or nitrosylated PDE inhibitors (as
described, for
example, in U.S. Patent Nos. 5,958,926 and 5,874,437, each incorporated herein
by
reference), or polymeric material that releases NO (as described, for example,
in U.S.
Patent Nos. 5,994,444 and 5,770,64, each incorporated herein by reference).
The
compositions of the invention may include more than one agent that increases
NO levels.
It is also known that inhibition of cyclic-GMP PDE(s), especially inhibition
of
PDE type 5 and type 6, promotes an increase in levels of cyclic-GMP (cGMP),
which in
turn fosters an increase in blood flow in the uveal system. This is
characterized by
increased blood flow velocity in the retina and the tissue surrounding the
optic nerve.
Thus, agents that inhibit cyclic-GMP PDE(s) also are useful in the methods of
the present
invention. The compositions of the invention may include more than one
inhibitor of
cyclic-GMP PDE(s).
Zaprinast and dipyridamole are both known to be inhibitors of the type 5 PDE
family and would, therefore, be expected to act to increase ocular blood flow
in the
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methods of the present invention. Other PDE inhibitors useful in the methods
of the
invention include filaminast, denbufyllene, piclimalist, pentoxyfilline,
carboline
derivatives (as described, for example, in U.S. Patent No. 6,043,252,
incorporated herein
by reference), pyridocarbazole derivatives (as described, for example, in U.S.
Patent No.
6,018,046, incorporated herein by reference) or quinozolinone compounds (as
described,
for example, in U.S. Patent No. 6,087,368, incorporated herein by reference).
It will also be understood that the compositions of the invention may include
a
combination of any of the above described agents.
The following more detailed discussion of a particular preferred compound for
use in the methods of the present invention is provided for illustration
purposes only and
is not meant to limit the scope of the invention. Those skilled in the art
will recognize
that agents described above, and other agents that act similarly, are useful
in the methods
of the invention.
A particularly preferred compound for use in accordance with the present
invention is sildenafil (preferably the citrate salt). Sildenafil is known to
cause smooth
muscle relaxation and an increase in blood flow, and is a selective inhibitor
of cyclic
guanosine monophosphate (cGMP)-specific PDE type 5 (PDE~). Sildenafil citrate
is
designated chemically as
1-[3-(6.7-dihydro-1-methyl-7-oxo-3-propyl-1 H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-
ethoxyp
henyl] sulfonyl-4-methylpiperazine citrate and has the following structural
formula:
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CH3(
aCH2CH;
CO~H
02S\N HOOCH
C02H
N\
\CH;
Sildenafil citrate is a white to off white crystalline powder with a
solubility of 3.5
mg/mL in water and a molecular weight of 666.7. Sildenafil citrate has most
recently
been utilized as the basis for an oral therapy for erectile dysfunction and
has been
marketed by Pfizer Labs under the trademark Viagra°. Publications
relating to benign
visual side-effects (e.g., blue-shift in vision, light-sensitivity, and
blurring noted to occur
in some patients) of sildenafil prompted the FDA to insist on product insert
warnings.
10 In spite of these side effects, the inventor hypothesized that sildenafil
might be
therapeutically beneficial in an appropriate setting. Elevation of cyclic-GMP
levels, a
potent vasodilator, is brought about by the effect of sildenafil on PDE
activity.
Appreciating this mechanism (i. e., the local effects of the PDE inhibitor on
intracellular
cyclic-GMP), and possible centrally-mediated neurogenic effects, the inventor
reasoned
15 that sildenafil could conceivably mediate significant increases in
choroidal blood flow.
Therefore, changes in vision and ocular blood flow were evaluated among a
dozen
clinician volunteers before and after taking 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.
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There were significant increases in pulsatile ocular blood flow (+29 percent;
from
916 +/-103 to 1185 +/-158 ~l/min; p<_0.02) and contrast sensitivity (+34
percent; from 92
+/-11 to 122 +/-11 log units; p<_0.01), 110 +/- 8 min after sildenafil
administration.
Retinal microcirculation increased in 7 of the 9 eyes in which there were
stable scans (+g
percent; p<_0.09). The results of perimetry did not change significantly, nor
did mean
systolic and diastolic blood pressure, systemic pulse amplitude, and
intraocular pressure.
None of the subjects reported any subjective visual symptoms (Sponsel et al.
2000).
Pulsatile ocular blood flow occurs as a result of cardiac-synchronous filling
of the
choroidal circulation, in which the majority of the ocular blood volume is
found. The
increase in pulsatile choroidal blood flow after sildenafil administration was
probably due
to dilatation of the choroidal vessels, because there were no changes in
intraocular
pressure or systemic pulse amplitude, other major determinants of choroidal
blood flow.
The mechanism associated with sildenafil citrate's use as a therapy for
erectile
dysfunction may explain its efficacious use in the methods of the present
invention. The
physiologic mechanism of erection of the penis involves release of nitric
oxide (NO) in
the corpus cavernosum during sexual stimulation. NO then activates the enzyme
guanylate cyclase, which results in increased levels of cyclic guanosine
monophosphate
(cGMP), producing smooth muscle relaxation in the corpus cavernosum and
allowing
inflow of blood. Sildenafil has no direct relaxant effect on isolated human
corpus
cavernosum, but enhances the effect of nitric oxide (NO) by inhibiting PDE
type 5
(PDES), which is responsible for degradation of cGMP in the corpus cavernosum.
When
sexual stimulation causes local release of NO, inhibition of PDES by
sildenafil causes
increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle
relaxation and inflow of blood to the corpus cavernosum.
Studies in vitro (by Pfizer) have shown that sildenafil is selective for PDES.
Its
effect is more potent on PDES than on other known PDEs (>10-fold for PDE6, >80-
fold
for PDEI, >1,000-fold for PDE2, PDE3, and PDE4). The approximately 4,000-fold
selectivity for PDES versus PDE3 is important because PDE3 is involved in
control of
cardiac contractility.
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3. Formulations for Use in Treatment of Ocular Disease States
Agents for use in the methods of the present invention may be delivered
orally,
parenterally, or may be formulated for direct topical application to the eye.
The use of
the term "applying" herein refers to any of the methods of delivery, including
orally,
parenterally, topically or otherwise. These delivery systems are effective to
administer
the compositions for use in the methods of the invention to the eye for the
purpose of
increasing optical nerve and retinal blood flow velocity. It will be
appreciated that in
accordance with the invention, the compositions can be administered by way of
a
solution, gel, semisolid, suspension, metered dose device, transdermal patch
or film.
Other means of delivery are also contemplated. The routes of administration of
sildenafil
citrate, for example, are typically oral and parenteral (including ophthalmic,
transdermal,
pulmonary, nasal, buccal, sublingual).
Preferred compositions for use in the methods of the present invention will
typically, but not necessarily, comprise a solution, gel, semisolid,
suspension, metered
dose device, transdermal patch or film including, for example, an agent that
enhances
ocular blood flow, a buffer system (e.g., hydrochloric acid, sodium hydroxide,
boric acid,
sodium borate, acetic acid, sodium acetate, sodium biphosphate, monobasic
sodium
phosphate, dibasic sodium phosphate, sodium carbonate, sodium acid phosphate,
disodium phosphate, sodium thiosulfate; 0.1 - 5 % of each, or the like), a
preservative
system (e.g., benzalkonium chloride 0.01 - 5%, benzethonium chloride 0.01 -
5%,
chlorobutanol 0.01 - 5%, methylparaben 0.01 - 5%, propylparaben 0.01
phenylmercuric
acetate 0.01 - 5%, phenylmercuric nitrate 0.01 - 5%, thimerosal 0.01 -sorbic
acid 0.01 -
5%, sodium perborate 0.01 - 5%, benzvl alcohol 0.01 - 5% or the like), an
absorption
enhancer system (e.g., polysorbate 80 0.00 - 6%, tocopherol TPGS 0.01 - 10'7c,
tyloxapol 0.005 - 6%, or the like), a stabilizer system (e.g., ascorbic acid
0.01 - S%,
tocopherol 0.01 - 5%, disodium ethylenediaminetetraacetate 0.01 - 5%,
tetrasodium
ethylenediaminetetraacetate 0.01 - 5%, or the like), a surfactant system
(e.g., polysorbate
80 0.00 - 6%, tyloxapol 0.005 - 6%, poloxamer 0.5 - 10%, or the like), a
viscosity-increasing system (e.g., polyvinyl alcohol 0.5 - S%, polyethylene
glycol 0.5 -
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5%, hydroxypropyl methylcellulose 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 I - 8%, propylene glycol 1 - 20%,
glycerin 1 -
20%, carbopol 1 - 10%, carboxymethyl cellulose 0.5 - 5%, lanolin alcohols 0.5 -
5%, or
the like), a gelling system (e.g., carbopol 1 - 10%, polyvinyl alcohol 0.5 -
5%,
hydroxypropyl cellulose 0.5 - 10%, hydroxyethyl cellulose 0.5 - 10%, methyl
cellulose
0.5 - 10%, poloxamer 0.5 - 10%, polyacrylamide 0.5 - 10%, hyaluroriic acid 0.5
- 10%,
gellan gum 0.5 - 10%, pectin 0.5 - 10%, or the like) , an osmolality adjusting
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 - 0.9%, or the like) and a vehicle (e.g., water, white
petrolatum; 5 -
99.9% for each).
While some compositions for use in the present invention may include all of
the
above listed elements, other useful compositions may include less than all of
the above
listed elements, which generally serve to increase stability, storability,
storage life, etc.
For example, it is contemplated that compositions including a compound that
enhances
ocular blood flow, i. e., by increasing NO, increasing cyclic-GMP, and/or
inhibiting
cGMP PDE, with a buffer system and a vehicle may be useful. Alternatively,
compositions including a compound that enhances ocular blood flow, with a
viscosity-
increasing system and an osmolality adjusting system may be useful. These
examples are
intended to be illustrative of certain preferred embodiments and are not meant
to be
exhaustive or limiting the scope of the invention in any way.
A preferred composition contains sildenafil citrate in an oral or ophthalmic
preparation such as those described above. For embodiments in which sildenafil
citrate is
administered orally, the sildenafil citrate will typically be present in
amounts ranging
from between about 5 mg to about 500 mg per dose. More preferably, the oral
dose will
contain from between about 10 mg to about 400 mg of sildenafil citrate, or
between about
15 mg and about 300 mg of sildenafil citrate or between about 20 mg and about
250 mg
of sildenafil citrate or between about 25 mg and about 200 mg of sildenafil
citrate. Most
preferably, the oral dose will contain about 50 to 100 mg sildenafil citrate.
It will be
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understood that a range, for example of between about 5 mg to about 500 mg,
includes all
integral amounts within the range, i.e., 6 mg, 7 mg, 8 mg, 9 mg etc., 30 mg,
31 mg, 32
mg, 33 mg, etc., 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, etc., 55 mg, 56 mg, 57 mg,
58 mg,
etc., 75 mg, 76 mg, 77 mg, 78 mg, etc. 101 mg, 102 mg, 103 mg, 104 mg, etc.,
150 mg,
151 mg, 152 mg, 153 mg, etc. 201 mg, 202 mg, 203 mg, 204 mg, etc, 220 mg, 221
mg,
222 mg, 223 mg, etc., 450 mg, 451 mg, 452 mg, 453 mg, etc., 475 mg, 476 mg,
477 mg,
478 mg, 479 mg, etc.
Preferred ophthalmic preparations of the present invention will generally
include
sildenafil citrate, for example, in concentrations of between about .001 % and
about 20
(weight per volume), including all amounts within the range. More preferably,
sildenafil
citrate will be present in the ophthalmic preparations in concentrations of
between about
.O1 % and 5 % and most preferably, the ophthalmic preparations of the
invention will
contain about 1 % sildenafil citrate. Of course, those skilled in the art will
understand that
the stated ranges include all amounts within the range, i.e., .02 %, .03 %,
.04 %, etc., .1
%, .11 %, .12 %, etc., .2 %, .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.,l5%,16%,17%,18%,19
etc.
Where desired, a convenient manner to deliver a metered dose is through the
use
of a device that is pressurized with a propellant system or is delivered by an
aqueous
pump spray. The propellant system may include 1,1,1,2-tetrafluoroethane (30 -
99.9%)
and/or 1,1,1,2,3,3,3-heptafluoropropane (30 - 99.9%) or other known
propellants. Where
employed, ethanol is typically used as a cosolvent (0.5 - 5%), although other
solvents
may also be useful in conjunction with the methods of the invention. The
preferred
median droplet size distribution for the pulmonary pressurized metered dose
inhaler is 2 -
5 microns and the preferred median droplet size distribution for the nasal
pressurized
metered dose inhaler is 10 - 20 microns.
Exemplary processes for formulation include the following:
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For the solution formulation, a quantity of an agent that enhances ocular
vascular
blood flow, such as sildenafil citrate (solubility of 3.5 mg/ml), is dissolved
in a portion of
the vehicle. The vehicle contains a cosolvent system to increase the
solubility of the drug
(agent that enhances ocular vascular blood flow) in the vehicle. The pH of the
solution is
adjusted and the solution is buffered. The solution is preserved and the
tonicity is
adjusted. The viscosity of the solution is adjusted by adding a viscosity-
increasing agent.
The final volume of the solution is adjusted using the remainder of the
vehicle. The
solution is packaged in an appropriate container/closure system to optimize
stability of
the drug substance and the integrity of the finished product.
For the gel formulation, the gelling agent is dissolved into an aliquot of
water. In
a separate portion of water, the drug, preservative, stabilizer, buffer and
osmolality
adjusting agent is dissolved. This blend is combined with the gel and stirred
until
homogeneous. The temperature may be elevated in order to enhance the mixing
process.
A high shear homogenizer is preferred to prepare the gel formulation. The drug-
containing gel is packaged in an appropriate container/closure system to
optimize
stability of the drug substance and the integrity of the finished product.
For the semisolid formulation, the vehicle is heated using low heat and the
preservatives are added to the molten vehicle mixture. The drug is then
incorporated
with continuous mixing into the molten vehicle mixture and homogenized at 2500
- 5000
psi. The preparation is removed from the heat source and continuously mixed
until
congealed at room temperature. The finished semisolid is packaged into an
appropriate
container/closure system to optimize the stability of the drug substance and
the integrity
of the finished product.
For the suspension formulation, an amount of micronized agent in excess of the
solubility (for example, more than 3.5 mg/ml of sildenafil citrate) is added
to an aqueous
vehicle containing the surfactant system, preservative system, buffer system,
osmolality
adjusting agent, and a viscosity increasing system. The suspension is
homogenized using
a high shear mixer (5000 psi pressure) until the drug is uniformly
distributed. The
finished suspension containing the agent that enhance ocular vascular blood
flow, is
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packaged into an appropriate container/closure system to optimize the
stability of the
drug substance and the integrity of the finished product.
It is contemplated that the container/closure system containing the
composition
will be included in a kit along with instructions for administration effective
to increase
ocular blood flow. The instructions will typically include directions for
dosage,
application, frequency and other relevant information pertinent to practice of
the methods
of the invention.
The film formulation (for delivery to the eye, skin, buccal cavity) is
prepared by
hot melt extrusion, cast film method, or other methods suitable for the
formation of thin
films. The preferred method is to mix the agent that enhances ocular vascular
blood
flow, such as sildenafil citrate, with a blend of thermoplastic polymers and
hot melt
extruding the drug containing mass through a suitable extruder. The thickness
of the film
is manipulated by the components of the formulation and by the operating
parameters of
the extruder. The film containing the drug is cut in a suitable size for
ophthalmic, buccal
or transdermal application, and packaged in an appropriate container/closure
system to
optimize the stability of the drug substance and the integrity of the finished
product.
Again, the film packaged in the container/closure system may be included in a
kit
along with instructions for application of the film effective to increase
ocular blood flow-,
or treat macular disorders, etc., as contemplated by the invention. The
instructions will
typically include such information as location of application of the film,
frequency of
application, time period of application, etc. The instructions may be printed
on the
outside of the container/closure system housing the film or may be included in
the kit
separately from the film container/closure system.
For the pressurized metered dose inhaler, agent that enhances ocular vascular
blood flow, such as sildenafil citrate, is mixed with ethanol, to produce a
"drug
concentrate" and an aliquot of the drug concentrate is dispensed into an epoxy-
lined
aluminum can (or lined Type I glass vial). The metering valve (20 - 150
microliter
preferably) is crimped onto the neck of the can. The propellant system is
filled through
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the valve. The canister is mated with an actuator (oral for pulmonary; nasal
for delivery
to the nose; ophthalmic for delivery, to the eye). Alternatively, the agent
that enhances
ocular vascular blood flow, such as sildenafil citrate, is administered in a
metered dose
aqueous dispersion using a pump. The drug is mixed with the surfactant and
water.
After mixing to dissolve the drug, a viscosity increasing agent is added and
the mixture
stirred. A preservative system is dispersed and the mixture is stirred. 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 should be appreciated by those of skill in the art that the
techniques
disclosed in the examples which follow represent techniques discovered by the
inventor
to function well in the practice of the invention, and thus can be considered
to constitute
preferred modes for its practice. However, those of skill in the art should,
in light of the
present disclosure, appreciate that many changes can be made in the specific
embodiments which are disclosed and still obtain a like or similar result
without
departing from the spirit and scope of the invention.
EXAMPLE 1
A 63 year-old man with dense pericentral visual field loss in the right eye
and
chronic excavatory optic neuropathy developed a new extension of his right
inferiotemporal scotoma on Humphrey 30-2 SITA-standard testing, splitting
fixation with
a threshold of 14 decibels in the macular zone of that quadrant. The patient
had
undergone over a dozen prior Humphrey field tests, showing perpetual
progression of
field loss despite maintaining intraocular pressures (IOP) from 6-10 mmHg
without
medication. Pericentral thresholds clockwise from superionasal were 26, 26,
14, and 25
dB (FIG. 6A).
Shortly after performing visual field and contrast sensitivity testing, the
patient
took a single 50 mg oral dose of sildenafil citrate (Viagra°°),
and repeated these visual
tests 110 minutes later. There was a dramatic resolution of the pericentral
perimetric
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defect, which increased in threshold from 14 to 23 decibels. The clockwise
progression
of pericentral threshold values was 28, 29, 23, and 26 dB, a mean increase of
3.75
decibels for the macular region loci, nearly a tenfold increase in light
sensitivity (FIG.
6B).
Central retinal contrast sensitivity measurements carried out before and after
sildenafil administration also showed remarkable improvement. Seven-degree
sine wave
patterns of 1 and 4 cycles per degree (cpd) at 15 reversals per second
(NeuroScientific)
were presented pre- and post-sildenafil. Three complete sets of training
contrast
sensitivity measurements in both eyes were carried out prior to testing. Low
threshold
values of 5.8 and 44.0, respectively, were obtained at 1 and 4 cpd in the eye
with
pericentral visual field loss (OD) before the drug was administered.
Thresholds in the
fellow eye were 10.0 and 92.3, respectively. 110 minutes after oral sildenafil
administration, left eye measures remained fairly constant, but those in the
eye with the
1 S pericentral perimetric defect (OD) increased dramatically to 31.2 and
92.3, respectively,
at 1 and 4 cpd. IOP and blood pressure were unaltered.
EXAMPLE 2
Another patient, an alert, 78 year-old retired professor of vascular surgery,
underwent pulsatile ocular blood flow measurements and Humphrey 10-2 visual
field
analyses prior to and one hour after ingestion of 50 mg oral sildenafil. In
his more-
diseased right eye, the entire superionasal visual field was a nonfunctional
absolute
scotoma, and 10 of the 17 of the superiotemporal quadrant loci also had
thresholds of
zero (FIG. 7A). Note the near total absence of visual function in the right
superionasal
visual field extending into the macular zone.
The patient's pulsatile ocular blood flow (POBF) in this eye was already
fairly
high, 1554 ~1/min. One hour after sildenafil ingestion, his right eye POBF
increased to
1975 ~l/min. The superonasal quadrant, previously blind, now exhibited
contiguous loci
with visual thresholds of 26, 28, and 27 decibels across the central six
degrees above the
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horizontal meridian, and 16 of the 17 superotemporal loci now had positive
thresholds,
15 of which were in double-digits (FIG. 7B).
EXAMPLE 3
Quite clearly, sildenafil citrate, even when administered orally, can
positively
influence blood flow and visual function for a very brief period of time.
Topical
application of compositions comprising the drug, yielded similar surprising
results:
A 45 year-old man with normal visual function, slit lamp and fundus findings
underwent Humphrey 10-2 full-threshold central visual field analysis and
contrast
sensitivity (seven-degree sine wave patterns of l and 4 cycles per degree at
15 reversals
per second; NeuroScientific) testing. The subject had undergone numerous
previous
Humphrey field and contrast sensitivity tests, eliminating the prospect of any
significant
learning effect on repeat testing.
Shortly after performing baseline visual field and contrast sensitivity tests,
he
received in masked fashion one drop of artificial tear solution to his right
eye, and one
drop of sildenafil solution (sildenafil 1% (10 mg/ml in Schein artificial tear
solution
buffered to pH 8.0)) to his left eye. He reported no discomfort with either
drop. and was
unaware which eye had received which agent. He repeated visual function
testing in both
eyes 100 minutes after receiving the eyedrops.
There was a dramatic increase in pericentral contrast sensitivity in the eye
receiving sildenafil, while the function of the placebo-treated eye remained
relatively
constant. Contrast sensitivity (CS) ratios to the 1 cycle per degree stimulus
were 203 in
the right eye and 235 in the left eye prior to treatment. The placebo-treated
right eye had
a CS ratio of 235 after 100 minutes, while the sildenafil-treated eye had a CS
ratio of 317
(p<0.0001). The increase in CS ratio to the 4 cycle per degree stimulus with
sildenafil
was similarly impressive, with values of 194 in the placebo-treated right eye
versus 581
in the sildenafil-treated left eye 100 minutes after treatment (p<0.0001 ).
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Humphrey 10-2 visual fields demonstrated a similar phenomenon. Despite the
left eye having a lower light sensitivity than the right prior to treatment,
it displayed a
significantly higher retinal light sensitivity than the right eye 100 minutes
after receiving
topical sildenafil. The pre-treatment mean threshold value for the 10 degree
visual field
5 in the left eye was 31.2 (+/-.19) decibels; 100 minutes after sildenafil
eyedrop application
this had increased to 32.7 (+/-.17) decibels (p<0.0001), a 70% increase.
Intraocular
pressures remained around 10 mmHg in both eyes and did not rise during the
study
interval. There were no adverse effects or significant visual symptoms
elicited, and
ocular appearance, pupil diameter. conjunctival and corneal appearance were
symmetric
10 and normal in both eyes.
EXAMPLE 4
FIG. 1A and FIG. 1 B represent patient data from three patients showing an
15 increase in retinal blood flow and blood velocity as measured using
scanning laser
doppler velocimetry. The data shows the increase over a period of time up to
about 85
minutes from administration of 50 mg oral sildenafil citrate (Viagra °
). FIG. 1A is a graph
of retinal blood flow as measured by Heidelberg Retinal Flowmetry (HRF) for
three test
subjects over time. FIG. 1B is a graph of retinal blood velocity as measured
by
20 Heidelberg Retinal Flowmetry (HRF) for three test subjects over time.
EXAMPLE 5
FIG. 2A and FIG. 2B represent patient data from two patients showing an
increase
25 in contrast sensitivity over a period of time up to about 75 to 125 minutes
from
administration of 50 mg oral sildenafil citrate (Viagra°). 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.
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EXAMPLE 6
FIG. 3A and FIG. 3B show an improvement in visual field response for two
separate individuals. The reports show both baseline (left side of each
figure) and
post-administration of 50 mg oral sildenafil citrate (Viagra°°).
FIG. 3A provides
Humphrey Frequency Doubling Technology (FDT) visual field reports for a first
test
subject baseline (left) and post-application (right) conditions. FIG. 3B
provides
Humphrey Frequency Doubling Technology (FDT) visual field reports for a second
test
subject baseline (left) and post-application (right) conditions.
Ti'Y A MPI Ti' 7
FIGS. 4A, 4B, SA and SB represent patient data from two patients showing other
relevant ocular data over a period of time up to about 100 to 200 minutes from
administration of 50 mg oral sildenafil citrate (Viagra ). Fig. 4A is a graph
of pulsatile
ocular blood flow for two test subjects over time. FIG. 4B is a graph of
intraocular
pressure measured concomitantly with OBF for two test subjects over time. Fig.
5A is a
graph of blue field density (perimacular retinal capillary circulatory volume)
for two test
subjects over time. Fig. 5B is a graph of blue field mean velocity
(perimacular retinal
capillary circulatory speed) for two test subjects over time.
Although the invention has been described with reference to specific
embodiments, this description is not meant to be construed in a limited sense.
Various
modifications of the disclosed embodiments, as well as alternative embodiments
of the
inventions will become apparent to persons skilled in the art upon the
reference to the
description of the invention.
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The following references, to the extent that they provide exemplary procedural
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