CA2369054C - Treatment and control of ocular development - Google Patents

Abstract

A composition for the inhibition of the abnormal postnatal axial growth of the eye of a maturing animal which comprises a pharmaceutically effective amount of a muscarinic pharmacological antagonist relatively selective for blocking the cholinergic receptos in cells of the brain, neural tissue and/or neural ganglia but less selective for blocking the cholinergic receptors of the cells of smooth muscles at the front of the eye, said antagonist present in a carrier or diluent suitable for ocular administration.
A suitable antagonist is pirenzepine. Other suitable antagonists are telenzepine and o-methoxy-sila-hexocyclium.

Description

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 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, 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.

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 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 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 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

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 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 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 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.

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 ' 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.

Claims (16)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE AS FOLLOWS:

1. Ocular use of an effective amount of a cholinergic agonist for inducing axial growth of the eye of a maturing animal.

2. The use of claim 1 wherein the cholinergic agonist is carbamyl choline chloride.

3. The use of claim 1 wherein the cholinergic agonist is pilocarpine.

4. The use of claim 1 wherein the cholinergic agonist is the M1 muscarinic agonist McNeil-A-343.

5. Ocular use of an effective amount of a cholinergic agonist for treating the eye of a maturing animal to inhibit or reverse the development of axial hyperopia.

6. The use of claim 5 wherein the cholinergic agonist is carbamyl choline chloride.

7. The use of claim 5 wherein the cholinergic agonist is pilocarpine.

8. The use of claim 5 wherein the cholinergic agonist is the M1 muscarinic agonist McNeil-A-343.

9. The use of a therapeutically effective amount of a cholinergic agonist in the preparation of a medicament for inducing the axial growth of the eye of a maturing animal.

10. The use of claim 9 wherein the cholinergic agonist is carbamyl choline chloride.

11. The use of claim 9 wherein the cholinergic agonist is pilocarpine.

12. The use of claim 9 wherein the cholinergic agonist is the M1 muscarinic agonist McNeil-A-343.

13. The use of a therapeutically effective amount of a cholinergic agonist in the preparation of a medicament for treating the eye of a maturing animal to inhibit or reverse the development of axial hyperopia.

14. The use of claim 13 wherein the cholinergic agonist is carbamyl choline chloride.

15. The use of claim 13 wherein the cholinergic agonist is pilocarpine.

16. The use of claim 13 wherein the cholinergic agonist is the M1 muscarinic agonist McNeil-A-343.