United States Patent (19) 11) Patent Number: 5,461,052 Stone Et Al
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USOO5461052A United States Patent (19) 11) Patent Number: 5,461,052 Stone et al. 45) Date of Patent: Oct. 24, 1995 54 PREVENTION OF MYOPIA BY TRICYCLIC OTHER PUBLICATIONS COMPOUNDS The Merck Index Eleventh Edition 1989, pp. 80 and 780. 75 Inventors: Richard A. Stone, Havertown; Alan European Journal of Pharmacology, 190 (1990) 1-9. Ikeda M. Laties, Philadelphia, both of Pa. Hoffmeister,et al. F. and Stille, G. Psychotropic Agents, Part 1: (73) Assignee: The Trustees of the University of Antipsychotics and Antidepressants, Zeelen, F. J., Chapter Pennsylvania, Philadelphia, Pa. 16, "Chemistry Structure and Activity", (1980). Springer-Verlag, New York, 1980. 21 Appl. No.: 55,202 Primary Examiner-Zohreh Fay Attorney, Agent, or Firm-Woodcock Washburn Kurtz 22 Filed: Apr. 30, 1993 Mackiewicz & Norris (51) Int. Cl. ................................... A61K 31/55 57) ABSTRACT 52 U.S. Cl. ............................................. 514/217; 514/912 58 Field of Search ...................................... 514,217,912. A composition for the inhibition of the abnormal postnatal axial growth of the eye of a maturing animal which com 56) References Cited prises a pharmaceutically effective amount of a tricyclic compound, said tricyclic compound present in a carrier or U.S. PATENT DOCUMENTS diluent suitable for ocular administration. Suitable tricyclics 4,865,599 971989 Chiou ...................................... 424/427 are tertiary amines, secondary amines, and other active 5,055,302 10/1991 Laties et al. ... 424/427 metabolites of tricyclic compounds. 5,122,522 6/1992 Laties et al. ....... ... 514/220 5,284,843 2/1994 Stone et al. ............................. 514/213 7 Claims, 1 Drawing Sheet U.S. Patent Oct. 24, 1995 5,461,052 TRICYCLIC AGENTS 0. 4. O. O so O. 4. O 6 AMTRIPTYLINE MPRAMNE NORTRIPTYLINE 2.48wg 2.5ug 2.3T?ug 5,461,052 1 2 PREVENTION OF MYOPIA BY TRICYCLIC myopia can be experimentally induced, in either birds or COMPOUNDS primates, in an eye in which the retina is deprived of formed images, e.g., by suturing the eyelids or wearing an image diffusing goggle. The experimental myopia induced in pri GOVERNMENT SUPPORT mates such as monkeys mimics the common axial myopia of This work was supported in part by research grants from humans. the National Institutes of Health-National Eye Institute, Thus, the phenomenon of an animal's vision process grant numbers EY05454 and EY07354. The United States apparently contributes to the feedback mechanism by which Government may have certain rights in this invention. postnatal ocular growth is normally regulated and refractive O error is determined. This indicates that this mechanism is BACKGROUND OF THE INVENTION neural and likely originates in the retina. Further, there is good evidence that the phenomena lends itself to an assay This invention relates to control of ocular development for potential therapeutic agents. and, more particularly, to the treatment of the eye to control U.S. Pat. No. 5,055,302, to Laties and Stone, discloses a the development of myopia (commonly known as nearsight 15 method of controlling the abnormal postnatal growth of the edness). eye of a maturing animal using vasoactive intestinal peptide It has been estimated that about one of every four persons (VIP), PH1 or analogues of these peptides. These peptides on earth suffers from myopia. About one-half or more of were found to inhibit axial elongation of a myopic eye. these cases are axial myopia, i.e., an elongation of the eye U.S. Pat. No. 5,122,522, to Laties and Stone, discloses a along the visual axis. 20 method of controlling the abnormal postnatal growth of the At birth, the human eye is about two-thirds adult size. eye of a maturing animal using pirenzepine. Axial elonga During the first years of life the eye is relatively short in the tion of a myopic eye was inhibited upon application of axial direction. As a consequence, young children tend to be pirenzepine. farsighted. During childhood, as the eye grows, there is a compensatory fine tuning of the optical properties of the 25 SUMMARY OF THE INVENTION cornea and lens to the increasing ocular length. Often the entire process is virtually perfect and no correction is needed The present invention provides methods for regulating the for sharp vision at distance; the eye is emmetropic. When growth of an animal's eye. The methods of the invention regulatory failure in this finely tuned process occurs, it comprise administration of an effective amount of a tricyclic usually goes toward a lengthened eye. As a result, distant 30 compound to the eye of an animal. This invention is more images focus in front of the plane of the retina and axial particularly pointed out in the appended claims and is myopia results. If, on the other hand, the regulatory failure described in its preferred embodiments in the following leads to an eye whose ocular length is too short, near images description. focus behind the plane of the retina and the result is hyperopia (commonly known as farsightedness). 35 BRIEF DESCRIPTION OF THE FIGURE Over the years, many theories have been put forth to FIG. 1 shows the effect of tricyclic compounds amitrip explain the development of myopia, e.g., inheritance, exces tyline, imipramine and nortriptyline in blocking axial sive near work, and environmental influences such as hours growth. of sunshine, diet, etc. From these theories many preventative 40 measures have been proposed including spectacles, eye DETAILED DESCRIPTION OF THE exercise, eye rest, cycloplegia, and other drug therapies. The INVENTION clinical literature on the subject is massive. Based on a theory that substantial use of the eye by In the ordinary visual function of the eye of an animal, children for reading leads to the development of permanent light forming an image passes through the lens and is nearsightedness or myopia, many remedies directed at the 45 received by the retina, a neural tissue embryologically focussing mechanism at the front of the eye have been related to the brain. The retina transmits this information to proposed. Largely these have been attempts either to block the optic nerve which sends it on to the brain. near focus through topical application of drugs or to remove Retinal neurochemicals (i.e., neuro-active chemical com any need for near focus through use of plus lenses that in pounds) are key ingredients in the vision process. Specifi effect perform the near focus task. Topical drugs that relax 50 cally, light forming the image is sensed by the light recep the focussing muscle of the eye, the ciliary muscle, are tors, the rods and cones, of the retina. These photoreceptors called cycloplegics and have been available for a century. act as transducers changing light energy into electrical Some clinical studies have suggested that atropine, a and/or chemical signals. long-acting cycloplegic, applied topically to the eye may 55 In the regular process of transmitting the image informa retard development of myopia. Atropine treatment, however, tion to the brain, retinal nerve cells, in association with the is not practical: it causes profound dilation of the pupil, photoreceptors, release neurochemicals and pass electrical which results in light sensitivity, and its action to inhibit signals transmitting information to adjacent retinal cells as ocular focussing impairs near visual work like reading. In parts of a network in the retina leading to the formulation addition, a dilated pupil causes discomfort to the patient. 60 and qualities of the signals that later go to the brain via optic There is now substantial evidence to validate the worth of IcWe. an experimental model of myopia and through its use to link The present invention is directed to a method of control the posterior part of the eye, specifically image quality at the ling the abnormal postnatal growth of the eye of a maturing retina and hence an extension of the nervous system, to the animal which comprises the ocular administration of thera postnatal regulation of ocular growth. There is significant 65 peutically effective amounts of a tricyclic compound, of the evidence of myopia resulting in an eye that is subjected to class or classes usually termed tricyclic antidepressants, see retinal image degradation. It has been shown that axial for example Hoffmeister, F. and Stille, G. Psychotropic 5,461,052 3. 4 Agents, Part 1: Antipsychotics and Antidepressants, Zeelen, example. This example is not to be construcd as limiting thc F. J., Chapter 16, "Chemistry Structure and Activity' scope of the appended claims. Springer-Verlag, New York, 1980. A method of inhibiting the abnormal postnatal axial growth of the eye of a maturing animal during conditions ordinarily leading to said abnormal EXAMPLE growth, which comprises administering to said eye during postnatal maturation a therapeutically effective amount of a Form-deprivation myopia was induced in day-old White tricyclic compound in a carrier or diluent buffered to a pH Leghorn chicks under aseptic conditions and ether anesthe suitable for ocular administration is also included in the sia. One eyelid of the chicks was sutured which does not present invention. completely block vision. Translucent vision is permitted 10 through the eyelid. The chicks were maintained on a 12 hour A composition for the inhibition of the abnormal postnatal light:dark cycle. The sutured eyes were treated with either axial growth of the eye of a maturing animal which com imipramine (2.5 ug), amitriptyline (2.48 ug), nortriptyline prises a pharmaceutically effective amount of a tricyclic (2.37 ug), or saline solution. The contralateral unsutured compound present in a carrier or diluent buffered to a pH open eye served as a control. The sample populations for suitable for ocular administration is an embodiment of the 15 imipramine, amitriptyline, and nortriptyline were n=8, n=6, present invention.