Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-07-06
2004-03-23
Pryor, Alton N. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S263100, C514S263200
Reexamination Certificate
active
06710051
ABSTRACT:
The invention relates to a method for identification of substances which are applicable for treatment or prevention of an insufficient longitudinal growth of the eye (hypermetropia) or for treatment or prevention of an excessive longitudinal growth of the eye (myopia); substances identified by the method for treating or preventing conditions related to the longitudinal growth of the eye; substances and mixtures of substances for the preparation of a pharmaceutical composition for the treatment or prevention of abnormal growth of the axial length of the eye.
BACKGROUND OF THE INVENTION
Myopia is caused by the length of the eye being too big in relation to the optical strength of the cornea and the lens so that the picture of a distant object is focused in a point in front of the retina, whereas the picture produced on the retina will be blurred. In other words, myopia is caused by an anomaly between the length of the eye (the axial length) and the refraction in the cornea and the lens.
The longitudinal growth of the eye (from approximately 17 mm at birth to approximately 24 mm) during the childhood is caused by expansion of the eye content and thus stretching the immature connective tissue in the sclera of the eye which adjusts to the new size of the eye. Normally the eye will reach its permanent length at the age of 12, at which time the connective tissue in the sclera reaches an appropriate degree of maturity and the longitudinal growth of the eye will stop.
In myopic persons the longitudinal growth of the eye is too high and the longitudinal growth of the eye continues for a longer period of time than in normal individuals. Hypermetropia is caused by the length of the eye being too short in relation to the optical strength of the cornea and the lens. Hypermetropia usually prevails at birth and is normally recorded at the age of 3-5 years. Subsequently it will reduce in proportion with the growth of the eye until the age of 12, from which age it will remain constant for the rest of the persons life.
Approximately 25%, of the population are myopic. In some myopic persons the axial length is normal (physiological myopia, of <−4 dioptry), in other persons, the axial length grows from the age of 8-10 unproportionally much until the approximate age of 20, and subsequently the axial length and thus the myopia are stable (intermediary myopia, glass strength of from approximately −4 to −6 dioptries).
Finally, in rare cases a continuously growing axial length throughout the entire life can be seen, often connected with bulges in weak areas of the eye wall (scleraectasies). Here the myopia can reach extreme levels for glass strengths of up to approximately −40 dioptries (Excessive/pathological myopia).
The intermediary form, and the excessive one in particular, is connected to a high risk of severe sight threatening complications such as e.g. retinal detachment, degenerative changes in the yellow spot of the eye (macula degeneration) and glaucoma.
In the Western part of the world, severe myopia is among the most important causes of blindness.
The group of myopic persons with a glass strength of more than −6, which comprises parts of the intermediary group and the entire excessive group, comprises approximately 2% of the population, e.g. in Denmark approximately 100 000 persons (Curtin, B. J.: The myopys: Basic science and clinical management, Harper and Row, Philadelphia, (1985)).
The cause of axial length conditional myopia is unknown.
It is however known that the longitudinal growth of the eye can be increased by disturbance of the image formation on the retina, eg. experimentally by sewing together the eye lids of test animals (visual deprivation) (Yinon, U., Current Eye Research, vol. 3, 4, 677-690, 1984).
Administration of dopaminergic substances (apomorphine) in test animals exposed to visual deprivation inhibits the development of myopia. (Iuvone, P. M., Invest. Ophthalmol., Vis. Sci., 32, 1674-77 (1991)).
U.S. Pat. No. 5,055,302, Laties and Stone, shows a method for control of abnormal postnatal growth of the eye of an animal with the application of vasoactive intestinal peptide (VIP), PH1 or analogues of such peptides. Such peptides were found to restrain the axial longitudinal growth of a myopic eye.
U.S. Pat. No. 5,122,522, Laties and Stone, shows a method for control of abnormal postnatal growth of the eye of an animal with the application of pirenzepine, an anticholinergic substance (M1 Muscarine antagonist). The axial longitudinal growth was inhibited by administration of pirenzepine.
PCT-patent application publication No. WO 94/25034, Laties and Stone, shows a method for control of abnormal postnatal growth of the eye of an animal with the application of tricyclical-substances (antidepressiva). The axial longitudinal growth was inhibited by administration of tricyclical substances.
However, in most cases myopia and hypermetropia are benign conditions which can easily be corrected by means of glasses. In order to justify a medical treatment of these conditions, such treatment must be effective at relatively low dosages and roughly without any side effects, accordingly, as application of VIP, dopaminergic anticholineric or tricyclical substances is connected to risk of side effects as, simultaneously, the substances have considerable psychochemical effects these prior art substances are not suitable for such treatment.
It is also a theory that the growth of the eye can be.caused by passive stretching of the scleral connective tissue (Norton, T. T., Invest. Ophthalmol. Vis. Sci., 37(3), S324 (1996), Siegwart Jr., J. T., Invest. Ophthalmol. Vis. Sci., 37(3), S324 (1996)). Thus it is been shown possible to trigger irreversible stretching of the sclera in young rabbits by increasing the intraoccular pressure but it is not possible to stretch the sclera in mature rabbits (Greene, P. R., ARVO Abstracts, 1978, p. 297). However, tests with reduction of the intraoccular pressure by means of beta-blocking eye drops in humans developing myopia have no effect (Jensen, H., Acta, Ophthalmol., Suppl. 200, 69 (1991)).
There is no model for animal experiments which precisely corresponds to the human conditions. As mentioned above, it is possible to provoke myopia in some animals, e.g. cats and chicken, by sewing together the eye lids of newborn animals, but partly this experimental myopia develops much more rapidly than in humans, and partly the biological age of the animal (newborn) does not correspond to the same age when the myopia typically occurs in human (8-12 years). Furthermore, in chicken the sclera is considerably anomalous as it partly consists of cartilage.
As the conditions of the eye related to the refractory system is extremely common and preventive treatment is to be applied to children, probably during years of treatment, effective substances should be very safe. Accordingly, it would be a considerable improvement if a method for identification of a number of substances having an effect on the longitudinal growth of the eye was available. Among substances such identified, it would subsequently be possible to select, appropriate substances characterized by high efficiency and few side effects.
The present invention is related to methods for identification of substances or groups of substances being candidates for the treatment or prevention of disease of the eye related to the longitudinal growth of the eye.
One of the methods for identification of effective substances according to the present invention is related to the fact that, developmentwise, the retinal pigment epithelium is a part of the retina and forms an electrochemically active cell layer which is located between the choroid membrane of the eye and the neuronal part of the retina (neuroretina). It forms an electrically tight barrier and due to active ion transport (based on the Na
+
-K
+
pump) it creates a difference in potential (the standing potential), the cornea-fundal potential, between the inner and the outer part of the eye of approximately 5 Mv.
Due to the ana
Cooper Iver P.
Klaus Trier APS
Pryor Alton N.
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