Note: Descriptions are shown in the official language in which they were submitted.
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TREATMENT AND CONTROL OF OCULAR pEVELOpMENT
BACKGROUND OF THE INVENTION
This invention relates to control of ocular
to development and, more particularly, to the treatment of the ,
eye to control the development of~myopia (commonly known as
nearsightedness).
It has been estimated that about one of every
four persons on earth suffers from myppia, About one-h~~,~
or-more of these cases are axial myopia, i.e,, an
elongation of the eye along the visual axis.
At birth, the human eye is about two-thirds ddN~t
size and is even at that site rel~tiv~l~ short in the ax~.~~
direction. As a consequence; young chi.ldr~n t~Dd to bs
2o farsighted. During childhood, as the eye grows, them is ~
compensatory fine tuning of the optical prop~rti~~ of
cornea and lens to the increasing ocular length. Often ~h
entire process is virtually perfect and no corx'ection ~~an
needed for sharp vision at distance; the eye ~s ~mmet~gp~g, ,~'
;:
When regulatory failure in this finely tuned process
CA 02369054 2002-02-15
2
occurs, it usually goes toward a lengthened eye, As a
result, distant images focus in front of the plane of the
retina and axial myopia results: If, on the other hand,
the regulatory failure leads to an eye who$e ocular length
is too short, near images focus behind the plane of the
retina and the result is hyperopia (commonly known as
farsightedness).
over the years, many theories have been put fort
to explain the development of myopia, e,g., inheritance,
to excessive near work, and environmental influences such as
hours of sunshine, diet, etc. F~c~m these the.or.i.es many
preventative measures have been proposed including
spectacles, eye exercise, eye rest, cycloplegia, and other
drug therapies. The clinical literature on the subject is
massive.
Based on a theory that substantial use of the dye
by children for reading leads to the deY~lopment of
permanent nearsightedness or myopia, many remedies directed
at the focussing mechanism at the'front ~f the eye have
2o been proposed. Largely these hate been ~ttempta either to
~rleck near focus through topical app~ic~~ion of drugs o~ ~tg
remove any need for near focus through uss of plus lenses
that in effect perform the near focus task: Topical drugs
that relax the focussing muscle of the axe, the cilia~y
muscle, are called cycloplegics and have been available for
a century.
Some clinical studies have suggested that
atropine, a long-acting cycloplegic, applied topieally to
the eye day retard development of myopia, Atropine
treatment, how8~rer, is not practical: it causes dilation
of the pupil, which results i~ light ser~~itiYity, and its
action to inhibit ocular focussing impairs near Visual work
like reading. In addition to the discomfort to the
patient, there are indications that exce~$ l.~ght can t~ar~t
the retina and questions have been raised concerning the
danger of the long-term use of atropine for other strong
cycloplegics) on the retina whey exposed to bright i,ight,
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There is now substantial evidence to link the
posterior part of the eye, specifically image quality at
the retina and hence an extension of the nervous system, to
the postnatal regulation of ocuier growth. These is
significant evidence of myopia resulting in an eye that is
subjected to retinal image degradation. It has been shown
that axial myopia can be experimentally ,induced, in either
birds or primates, in axe eye in Which the retina ~.
deprived of formed images, e,g., by eutu~ing the eyeli.de o.r
~.0 Wearing an image-diffusing goggle. The experimental mypp~e
induced in primates each as monk~ye pre~~.sely mi..mics the
common axial myopia of humans.
Thus, the phenomenon of an en~~na1's vision
process apparently cont~ib~tes tp the feedback mechanism by
Which postnatal ocular gFowth ~.s normal~.y regulated a~ld
refractive error is deteram~.~ed, This in~i~at~s that the
~nechan~sm ~.s neural at~d .~.~.kely 4~ic~inati~e ~r~ the x~et~na,
In the patent pf R.A, $tone, ~,~~t. ~,$tiee ax~c~ P,M.
Iuvone, Canadian Patent l, 33fi, ~9Q, a ~net~,oc~ of Qon~xcl~.i~g
the abnormal postnatal growth of the eye of a maturing
animal was found which comprises ~contro~.~.ing the presenoe
of a neurochemical, its agonist qr antagon3.st, which
neurochemical is found to be changed under condit~.ons
during maturation leading to abnormal axial length.
Therein it is disclosed that in experimental animals, such
as chicks or monkeys, Subjected to ocular image depr~va~ion
. ordinarily leading to the development of myopia, the
metabolism of certain retinal ne~~-ochemicals is altered
~.eading to changes in retinal concent,rat~.ons thereof.
Specifically, retinal concentrations of dopamine were found
to be reduced during such image cie~rivatior~ and the ocular
administration of a dopamine-reletsd agent, e.g.,
apomorphine, a dopamine agonist, was foynd to il~hibit o~
actually prevent the axial enlargement o~ the eye under
conditions ordinarily leading to such et~~argement.
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There have been recent advances made in the
understanding of the cholinergic ner~ou~ system.
Cholinergic receptors ire proteins embedded in the wall of
a cell that respond to the chemical acetylcholine. They
are broadly broken doW~ into nicotinic anc] muscarinic
receptors. In this respect, it is now known that the
muscarinic receptors are not all of one ~.y~e. Recent
findings show that there are at least five, if not more,
types of cholinergic uluscax~inic x~ecepto~s (types M, t~r4ugh
to Ms). Type M, receptors are those present in abundance at~d
thought to be enriched in the braip neux~l. t,i.~su~. arid.
neural ganglia. other receptors are copce~trated in other
tissues, such as in heart, smooth muscle tissue, or glands.
While many pharmacological agents interacting with
muscarinic receptox-s influence several ~yp~s, ome are
known to have a major effect on a single type of receptor
with relative selectivity and other agents can have a
relatively selective effect on a different single receptor,
Still other agents may have a significaHt effect on mo~r~
than one or even all t~rpes of receptors, A pharmacological
antagonist, for the purposes of this discussion, is art
agent that effectively blocks the receptor. It is known
that pirenzepine, (Gastrozepin, LS 519) 5,11-Dihydro-11-[4-
methyl-1-piperazinyl)acetyl]-fiH-pyrido[2,3-
b][1,4]benzodiazepin-6-one; and its dihydrochloride, are
known as anticholinergic, selective M, antagonists. It is
further known that telenzepine, i.e., 9,~-dihydro-3-methyl-
9[ (4-~uethyl-(1)piperazine)acetyl.]1oH-th~.~no-X3,4--b] ~1,5~-
benxodiazepin-10-on, and its di~ydrochlo~ide, are also
known as anticholinergic select~.~e Ml ~nt~gonist$ reported
to be about ten times a$ potent as pirer~~r~pa.He. (See Euro.
Jour. of Pharmacology, x,65 (189) 87-~6.) It is also known
that 4-pAMP ( 4-diphenylscetoxy-~-~neth~lp~~arad~.~e
methiodide) is a selective antagonist for smooth muscle
f5 (ordinarily called M3 type but variously called type M~ or
M3, as the current classification o~ receptors is 'in flue ,
a
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a _ . 5
It is believed that atropine is an antagonist for all types
of cholinergic muscarinic receptors.
SUMMARY OF THE INVENTION
It has been found in accordance with this
invention that the growth of an animal's eye can be
inhibited or regulated by a muscarinic pharmacological
agent of a type particularly effective in brain, neural
tissue and/or neural ganglia, which agent is relatively
less effective toward most $moo~h muscles such as occur at
to the front of the eye and in other location. Th,i~
invention is more particularly pointed ot~t in the appended
claims and is described in its preferred embodiments in the
following description:
DETAILED DESCRIPTION OF THE INVENTION
In the ordinary visual function of the eye of an
animal, light forming an image passes through the lens and
is received by the retina, a neural tissue embryologically
related to the brain. The retina transmits this
information to the optic nerve which sen~$ it on to the
brain.
Retinal neurochemicals (i.e., neuro-active
chemical compounds) are key ingredients in the vision
process. Specifically, light for~ni#~g the image is sensed
by the light receptors, the rods and cones, of the retina.
These photoreceptors act as transducers changing light
energy into electrical and/or chemical signals.
In the regular process of transmitting the image
information to the brain, retinal nerve cells, in
association with the photoreceptors, release neurochemicals
3o to pass information to adjacent retinal cells as parts of a
network in the retina leading to the formulation and
qualities of the signals that later go to the brain Via
optic nerve.
In accordance with this invention, it has been
found that the anticholinergic muscarinic antagonist
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pirenzepine, known to be have a relatively selective
affinity to,type M, receptors as in neural structures but
relatively low affinity for smooth muscle muscarinic
receptors, can be effective in blocking the axial-
elongation myopia ordinarily produced by ocular image
deprivation in the chick. In separate experiments, it has
been noted that topical or systemic administration of
pirenzepine has relatively little effect on the iris (i.e.,
little pupil dilation) . Similarly,. pirenzepine has
l0 relatively little effect on the heart rate or esophageal
motility in monkeys or humans.
Telenzepine; an even more potent selective M~
antagonist which shows little affinity for M3 smooth muscle
receptors, is another example- of an agent which can be used
to block axial-elongation myopia in a maturing animal.
Because of its greater potency, it may be possible to use
smaller amounts of telenzepine to, achieve a similar effect
to that caused by piren2epine treatment.
Another muscarinic antagonist that can be used as
an agent to block axial-elongation myopia is o-methoxy-
sila-hexocyclium, i.e., 4-([cyclohexylhydroxy(2-
methoxyphenyl)silyl]methyl}-1, 1-dimethylpiperazinium
methyl sulfate. See Euro. Jour. pharm., 151 (1988) 155-
156. This agent often referred to as o-MeSiHC, is known to
be an antagonist for Ml muscarinic receptors With
substantially. less effect on smooth muscle receptors whose
selectivity in that respect has been reportgd to be higher
than pirenzepine. Again, this may enable the use of
smaller amounts to achieve a similar effect in the
inhibition of axial-elongation myopia.
Many other potent antagonists for M1 muscarinic
receptors are known. Most, however, like atropine also
shaw substantial effects on M3 smooth muscle receptors, If
this effect is significant, the discomfort end disability
resulting from their use for ocular treatment render their
use impractical, at best, and possibly harmful.
ordinarily, the effect of a muscarinic agent on M, smooth
CA 02369054 2002-02-15
7
muscle receptors can be observed by its dilation of the
pupil. upon ocular administration. If the therapeutically
effective amount of the agent applied for treatment results
in.a dilation of the pupil by 2 ~nm or more, this side
effect is likely to limit its use.
As stated herein, the muscarinic agents for use
in this invention are those relatively selective in
blocking the type Ml receptors which do not select for the
type Mj smooth muscle receptors. In generals a suitable
to agent will have at least five time greater affinity for Ml
receptors than for M3 smooth ~u~rl~. r..t~.rs, preferable
more than to times greater. Pirenzepine, telenzepine and
o-MeSiHC are representative of preferred agents. The
affinity and relative affinity of ~nuscarinic antagonists
for M1-MS receptors can be determined by means known in the
art. See Buckley et al., Molecular Pharmaco~.ogy, 35: 969-
4~6 (1989) for a detailed description of techniques know
in the art for determining the antagonist binding
properties of five cloned muscarinic receptors. Similarly
there are many ways in'which to accomplish functional
studies to measure Ml sensitivity., For instance, one
popular method at present is to use vas deferens of the
guinea pig which has an Ml sensitivity. First it is set up
so that its tension is, measured and a known stimulator.such
as the M, agonist McNeil A393 is given to change tension by
a predictable amount. Under this ca#~dition, the predicted
effect of the agonist is first carefully plotted and then
the degree to which one or another antagonist blocks this
agonist effect is ri~easured. In a specific experiment of
3o this kind, pirenzepine was shown to have a strong blocy~ing
effect and thus demonstrable M, antagonist quality.
For the purposes of comparison in chick myopia,
companion experiments were run using the ocular
administration of 4-DAMP, a m~scarinic antagonist having an
affinity profile distinct from pirenzepine; ~-DAMP is
recognized for its effect on smooth muscle receptors, e.g.,
that of the bronchus or ileum. It was found that 4-DAMP
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does not block the axial-elongation myopia ordinarily
produced by image deprivation in the chick. It was found,
conversely, in separate experiments in rat ,and monkey after
topical-application of effective amounts to the eye that 4-
DAMP is a potent dilating agent for the pupil. It is
expected that similar muscarinic antagonists effective in
blocking the receptors of smooth muscle tissue (e.g., of
gut and bronchus) would be similarly effective as pupil
dilating agents.
to Differences in effect between piren2epine and 4-
DAMP in the chick model of experimenta,L myopia lie.at the
core of the present invention. Pirenzepine would be
expected to be more selective for central nervous system
tissues such as brain (arid retina) while 4-DAMP would be
expected to be more selective for smooth muscle as irt ileum
or iris. Comparison of the differeDtial ocular effects
after local administration versus the profiles of the two
drugs are interpreted as independent evidence ,for the
retinal hypothesis for axial myopia in lid-sutured chick.
2o In short; it forms the basis for a claim stating that
pirenzepine and like drugs with similar relative
selectivity for neural muscarinic receptors can inhibit the
development of axial elongation of the eye as witnessed ~,n
our chick experimental model, while drugs with selectivity
directed strongly at other receptor subtypes, especially in
smooth muscle tissue, do not. This invention is now
described 3~y the following example thereof:
EXAMPLE
Form-deprivation myopia was induced in day-oid
White Leghorn chicks under aseptic conditions. and other
anesthesia by eyelid suture to one eye. The chicks were
maintained on a 12 hour light: dark cycle. The sutured eyes
were treated with either pirenzepine or 9-DAMP at
concentrations listed in Table T or saline solution as a
control. Drug was injected daily subconjunctivally dining
the light cycle. At two weeks of age the animals were
sacrificed and axial and'equatorial dimensipns of unfixed
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g
eyes were measured with vernier calipers independently by
two observers. Lid-sutured chick eyes treated with 4-DAMP
developed axial elongation while those treated with
pirenzepine had a virtual blockade of axial elongation.
The following table illustrates the effects of drug therapy
on the growth of lid-sutured chick eyes. The average
increase in axial length is the difference; deprived eye
minus contralateral unsutured eye, for the number (n) of
animals tested.
TABLE I
Increased
Drug Dose(ua) ~xi~l length (mm.) n
pirenzepine 3.5 0.07 19
" 0.35 0.18 13
0.035 0.23 10
0.0035 0.29 10
4-DAMP 3.5 , 0.29 22
" 0.35 ~ 0.36 7
Saline solution -- 0.36 30
Based on a one-way analysis of variance, there is
significant effect on axial length (p<0.0o1 for pirenzepine
at 3.5 ~Cg/day and p<0Ø2 for pirenzepine at 0.35 ~eg/day)
and no significant difference for;the two groups treated
with 9-DAMP.
It is expected that the known muscarinic
antagonists telenzepine and o-MeSiHC can be used in the
above example in place of pirenzepine to obtain similar
results in the inhibition of axial growth of the chick
during maturation. Because of their reported more potent M1
receptor activity, it is expected that these.two agents may
be as effective as pirenzepine at lower dosage amounts.
Treatment to inhibit axial-elongation myopia
during maturation of an animal can be administered by the
use of the agent in eyerdrops. Indeed, in the vast
majority of cases, treatment agents are adm,iniste~ed to
human eyes by the application of eye drops. Eye drops ads
typically made up at a concentrat~.on of active agent
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to
between about o.5 and 2 percent in the ophthalmic medium.
A 1 percent solution of pirenzepitle (or other agent) in
Water would be a likely concentration for clinical use.
Some constraints in formulation may exist having to do with
pH and preservative. .A pH of about 6.5 is expected to be
acceptable as an ophthalmic drop and practical in terms of
known solubility and stability of pirenzepine. Since
pirenzepine and telenzepine are known to form very acidic
solutions in physiological saline, treatment With known
to compatible bases to bring the pH up to about a.5 to 7.5
(preferably 6 or 6.5) is recommended. phosphate buffetitlg
is also common for eye drops and is compatible With
pirenzepine and telenzepine. other additives and
ingredients may be present, e.g., those disclosed in Chiou;
U.S. Patent 4,865,599, at column 3, lines 7 to 50.
A Gammon
regimen for application of eye drops is two to three tithes
a day spaced evenly throughout waking hours. More
effective agents may require fewer applications or enable
the use of more dilute solutions. Alternatively;
ointments, solid inserts and local depositors of powders
are now coming into increased use i~t clinical practice.
They avoid problems of drug decomposition while delivering
a defined amount of drug. It is, of course, also possible
to administer the above-described active agents in
therapeutically effective amou»ts and dosages in pills,
capsules, or other preparations for systemic
administration.
. R
It should be noted that pirenzepine sloares With
other tricyclics a good safety profile. It has' been
reported to be tolerated Well in systemic use by most
patients with minimal side effects.
Since pirenzepine is generally xecograized ~s
remarkably selective for brain and other rfeurai siteg,
while ~-pAMP is recognized mainly for its functional effect
at smooth muscle, the differing results from tie
application of the two drugs suggest a neural, probably
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1~
retinal effect as responsible for the blockage of axial
elongation. Moreover, it has.been found that 4-DAMP has
stranger physiological effect o~ the anterior segment of
the eye whereas pirenzepine has much weaker effects in this
regard . On this basis, emphasis is placed on events at the
back of the eye as opposed to the front in the genesis of
axial elongation. Our present result could in no Way be
predicted beforehand. The selective action of pirenzepine
(sometimes termed an M, antagonist) toward the blockage of
expected axial elongation constitutes the present
invention. It is possible that piren~epi.ne ~t~. its.
observed effect by action at a locus other than the retina,
For instance, it could directly affect the synthesis of the
constituents of the outer-coat of eye, the sclera:
In addition to the aforementioned, we have also
found that under certain circumstances local administration
of a drug to one eye of,a chick with both eyes open (vision
unimpeded) causes a selective axial elongation of the
treated eye. Specificall~r we have administered known.
cholinergic aganists, carbachol (carbamyl choline chloride,
i.e., 2-[(aminocarbonyl)]-N,N,N,- trimethylethanammonium
chloride); pilocarpine (3-ethyldihydro-4-[(1-methyl-1H-
imidazal-5-yl[methyl]-2(3H)-furanone), and the Ml muscarinic
agonist McNeil-A-343(the compound (9-hydroxy-2-butynyl)-1-
trimethyiammonium
m-chlorocarbanilate chloride), on a once a day regimen as
indicated in Table II below. Each of the drug-treated eyes
was longer than its vehicle-treated fellow.
It is common to admi~rister these agents in the
form of their salts, e.g., hydrochlorides or nitrates, or
less commonly, their esters. The use of an M, muscari~ic
agonist, e.g., McNeil-A-:343 is likely to cause less
stimulation of the chol.inergically sensitive smooth muscles
at the front of the eye.
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12
TAHhE II
Muscarinic Effects on Growth of open Eyes.
ocular Dimensions (me~rn ~ 6.E.M,)
drug-treated minus vehicle-treaded eye)
Daily Increased Eguator~.at
Dose Axial Length Diameter
rug ~ ~mm1 ~~mL
carbachol 0.15 0.20 ~ 0.03 0.07 ~ 0.04 9
pi.locarpine 2.0 0.09 ~ 0.04 -0.004 ~- 0.03 ?
0.2 0.11 ~ 0.03 -0.02 ~ 0.03 10
0.02 0.18 + 0.08 0.05 + 0.04 9
McN-A-343 0.3 0.18 ~ 0.08 -0.04 ~ 0.02 10
Treatment with 1.5 ~Cg carbachol produced about 0.14mm axial
increase in 6 treatments.
In addition to the foregoing, tests were run With
a combination of an agonist, 0.15~eg carbachol, and an, Ml
antagonist, 0.3~g pirenzepine. The results indicated no
significant treatment effects an the axial and equatorial
length. This is evidence in favor of the finding that Ml
muscarinic receptors are involved in stimulation and
inhibition of ocular growth.
The increase in axial length observed in the
open-eye experiments could be important in the treatment of
children with conditions that lead to abnormally small eyes
and for individuals with far-sightedness (hyperopia) based
on inadequate axial length of the eye.
A description of cholinergic agonists is
contained chapter 5 "Cholinergic Agonists~' by Palmer Taylor
in ha aceutic 1 as's o Ther eut'cs, 7th Ed. Macmillan
Publ. (1985) edited by Goodman and Gilman.
In experiments in animals such as those mentioned
hereinabove in which axial myopia has been experimentally
induced by depriving the retina of formed images, it has
been noted by others in primates that amblyopia was also
experimentally and coincidentally induced. Amblyopia is
CA 02369054 2002-02-15
' 13
evidenced by poor visual acuity in the eye resulting in
poor visual performance. Normalcy, visual acuity improves
during maturation. It is known that amblyopia may occur in
humans from unknown causes or as part of strabismus: It is
possible that administration of therapeutically effective
amounts and dosages of the musca~i~ic antagonists
relatively selective in blocking the Ml chollnergic
receptors but less selective in ~lQcking Cholinergic
receptors in smooth muscle cells a,g., pi~enzepi~e,
1o telenzepine and o-methoxy-sila-h~xocyclium, fight preve~~
or inhibit the development of pe~nanent o~ per~i~.
amblyopia,in maturing human. It ~s alao possible that
humans who have already developed amblyopia from other
even unknown causes might be aided ~y similar therapeutic
treatment with the aforementioned agents.
