353 Atropine and Other Pharmacological Approaches to Prevent Myopia
Table 2. Observed Frequency of Subjects with Various Genotypes Stratified by Myopic Progression
Genotype at |
|
|
|
rs2067480 (First 2 |
No of Subjects: SE |
No of Subjects: SE |
|
Alphabets) and |
Worse by at Least |
Worse by Less Than |
Total |
rs542269 (Third and |
0.5 D |
0.5 D |
No. of |
Fourth Alphabet)* |
(Non-Responders) |
(Responders) |
Subjects |
|
|
|
|
CCTT |
25 |
39 |
64 |
CTTT |
4 |
10 |
14 |
TTTT |
0 |
1 |
1 |
CCCC |
0 |
1 |
1 |
CCCT |
4 |
16 |
20 |
CTCT |
0 |
2 |
2 |
NNNCa |
0 |
3 |
3 |
Total |
33 |
72 |
105 |
|
|
|
|
*Rows indicate the genotypes at the 2 loci: the first two letters represent the genotype at rs2067480 genotype at rs542269. The genotype at each locus is specified by 2 letters or bases, one for each of the 2 chromosomes. 18 subjects were found not have enough DNA to determine the allele at rs2067480, so only 102 subjects have genotypes examined at rs2067480.
aThis genotype consists of a “C” at rs542269, which can be heterozygous or homozygous for “C”. The genotype at rs2067480 is irrelevant for this genotype, represented by “NN” in the table. These subjects can be included in the analysis regardless of their genotype at rs2067480, or when the genotype at rs2067480 is not known. As a result of this qualification, 3 children’s data could be included in the analysis, which increased the total number of children analysed to 105.
SE: spherical equivalent.
This table shows the number of subjects with the specified genotypes (in rows) that were drug responders or otherwise. The last row shows the total number of responders (72) and non-responders (33).
SNPs at the other muscarinic receptor subtypes. Nevertheless, the current data are sufficiently interesting to suggest that SNP evaluation, as part of pharmacogenetic testing, should be incorporated into larger drug trials in myopia, with sample sizes that will allow sophisticated statistical procedures on multi-dimensional data.46
Potential Side Effects
The adverse effects of the use of 1% atropine has been reported to include photophobia and reduction of outdoor activities.16 Adverse side effects with 0.5% atropine was relatively reduced, and no apparent photophobia
354 L.M.G. Tong, V.A. Barathi and R.W. Beuerman
Table 3. Two by Two Contingency Table showing Test Result and Effectiveness of Treatment
|
Non-Responders: |
Responders: Intervention |
|
|
Intervention not |
Effective [SE Worsened |
|
|
Effective [SE Worsened |
by Less Than 0.5 D |
|
|
by at Least 0.5 D Over |
(or any Improved) |
|
|
2 Years] |
Over 2 Years] |
Totala |
|
|
|
|
NEGATIVE TEST* |
29 |
49 |
78 |
|
|
|
(74%) |
(rs2067480: CC or |
|
|
|
CT) and rs542269 TT |
|
|
|
POSITIVE TEST* |
4 |
23 |
27 |
|
|
|
(26%) |
Any genotype not |
|
|
|
covered above |
|
|
|
Totalb |
33 (31%) |
72 (69%) |
105 |
*The data for this 2×2 contingency table were obtained by collapsing or merging the genotypes (rows in Table 2), the first 2 rows in Table 2 were combined to produce the genotypes representing a negative test in Table 3, and the bottom 5 rows in Table 2 have been merged to produce the positive test genotypes. The reason for designating the genotypes in the first 2 rows as a “negative test” is that under these circumstances the proportion of non-responders (defined as having progression of more than 0.5 D) was higher than those of the other genotypes. In the cases with genotype CCTT (Table 2, first row), 39% were non-responders, and the cases with genotype CTTT (Table 2, second row), 29% were non-responders, whereas in all other genotypes (Table 2, subsequent rows), only 20% or less were nonresponders.
aPercentages in column indicate the proportion of people with negative and positive test results, not the proportion of responders. More people obtained a negative test compared to a positive test in this trial. bThis row indicates the percentages of responders and non-responders to treatment. More people respond to treatment than not.
was observed with 0.25% and 0.1% atropine.38 One possible side effect of unilateral use of atropine is the resulting anisometropia, especially if the untreated eye is rapidly progressing in myopia severity. In clinical practice, there is an option to switch unilateral therapy to the opposite eye, or to commence bilateral atropine treatment.
Another side effect that has been noted with 1% atropine eyedrops is the effect of cycloplegia or reduction of near visual acuity. A study in Singapore has shown that this complication is well tolerated largely.19 Nevertheless, atropine eyedrops are not recommended for all myopic children.4 This is because the long-term potential side effects of atropine such
355 Atropine and Other Pharmacological Approaches to Prevent Myopia
as cataract formation and retinal toxicity have not been evaluated. The electrophysiological assessment of some patients with atropine treatment showed little long-term effect, with the retina-on response changed more than the retina-off response.47
In the pirenzepine study,14 11% (31/282) of pirenzepine-treated subjects were discontinued from the study for adverse events.14 There were 15 serious adverse events reported in 12 subjects (all in the active groups), but none was ophthalmic in nature; all the subjects recovered, and only 1 (abdominal colic preceded by a flu) incident was possibly related to the treatment.
The use of timolol in myopia has been linked to stinging sensations and even bronchial asthma.42 This may be one reason why the scientific community has not pursued the use of ocular hypertensives in myopia.
The Future of Drug Treatment in Myopia
The mechanism of atropine in retarding the progression of myopia is not clearly understood. The original rationale for using atropine in myopia was the paralysis of accommodation to achieve slowing of myopia progression. However, atropine can still be effective in animal models following destruction of mid-brain nuclei and paralysis of accommodation.48 There are possible alternative mechanisms or multiple mechanisms, such as the remodeling of scleral connective tissue via a retinal or scleral mechanism.
Although atropine and pirenzepine are known muscarinic antagonists and these receptors are present in the eye, including the sclera, it is not known if the anti-myopia effects of these drugs are mediated principally by muscarinic receptors. Even if muscarinic receptors mediate the beneficial effect observed clinically, it is still unclear what subtype of muscarinic receptor or what signaling events are critical for the effect.
The future of drug treatment in myopia will be influenced by further development in the understanding of the basis of myopia development as well as the pharmacology, and cell and molecular biology of myopiagenesis. With the increased understanding of these areas, more targeted, safer and more effective treatment can be developed. An attractive idea is the customization of pharmacological treatment to different individuals. Since there is a genetic component to myopia development, there may also be differences in response to drug treatment. Such difference may be
356 L.M.G. Tong, V.A. Barathi and R.W. Beuerman
uncovered, for example, by genetic testing of single nucleotide polymorphisms. In addition, pharmacological treatment may be complementary to other behavioral treatment such as lifestyle modification or increase of outdoor activities.
What is the aim of pharmacological treatment in myopia? Most clinical trials in myopia currently evaluate the progression of myopia. This is a logical approach because the sight-threatening complications of myopia such as macular degeneration and retinal breaks increase tremendously with high myopia. If myopia can be arrested at an earlier stage, it may become a purely optical problem that is amenable to glasses or refractive surgical procedures. With increased understanding of myopia pathogenesis, it may be possible to shift the aim of treatment to the prevention of the onset of myopia. This type of preventive treatment, for example, may be employed in susceptible children with a family history of high myopia and other risk factors.
Conclusions
Myopia is a common ocular condition affecting many people, and recently attention has focused on the high prevalence and incidence of childhood myopia. Pharmacological treatment of myopia involves the use of various types of eyedrops but clinically, the most effective form of treatment is the use of atropine eyedrops. The aim of treatment with atropine eye drops is to retard the progression of myopia. Although this form of treatment can be judiciously used in suitable children, the optimal regime of administration of atropine eyedrops remains to be shown.
References
1.Goss DA. (1982) Attempts to reduce the rate of increase of myopia in young people — A critical literature review. Am J Optom Physiol Opt 59(10): 828–841.
2.Curtin BJ. (1985) The etiology of myopia. The myopias. Basic science and clinical management. Philadelphia: Harper and Row.
3.Saw SM, et al. (2000) Myopia: attempts to arrest progression. Br J Ophthalmol 86(11): 1306–1311.
4.Saw SM, et al. (2002) Interventions to retard myopia progression in children: an evidence-based update. Ophthalmology 109(3): 415–421.
357Atropine and Other Pharmacological Approaches to Prevent Myopia
5.Horner DG, et al. (1999) Myopia progression in adolescent wearers of soft contact lenses and spectacles. Optom Vis Sci 76(7): 474–479.
6.Ong E, et al. (1999) Effects of spectacle intervention on the progression of myopia in children. Optom Vis Sci 76(6): 363–369.
7.Katz J, et al. (2003) A randomized trial of rigid gas permeable contact lenses to reduce progression of children’s myopia. Am J Ophthalmol 136(1): 82–90.
8.Khoo CY, Chong J, Rajan U. (1999) A 3-year study on the effect of RGP contact lenses on myopic children. Singapore Med J 40(4): 230–237.
9.Polse KA, et al. (1983) Corneal change accompanying orthokeratology. Plastic or elastic? Results of a randomized controlled clinical trial. Arch Ophthalmol 101(12): 1873–1878.
10.Angi MR, et al. (1996) Changes in myopia, visual acuity, and psychological distress after biofeedback visual training. Optom Vis Sci 73(1): 35–42.
11.Yang Z, et al. (2009) The effectiveness of progressive addition lenses on the progression of myopia in Chinese children. Ophthalmic Physiol Opt 29(1): 41–48.
12.Hasebe S, et al. (2008) Effect of progressive addition lenses on myopia progression in Japanese children: a prospective, randomized, double-masked, crossover trial. Invest Ophthalmol Vis Sci 49(7): 2781–2789.
13.Bedrossian RH. (1979) The effect of atropine on myopia. Ophthalmology 86(5): 713–719.
14.Tan DT, et al. (2005) One-year multicenter, double-masked, placebocontrolled, parallel safety and efficacy study of 2% pirenzepine ophthalmic gel in children with myopia. Ophthalmology 112(1): 84–91.
15.Manny RE, et al. (2001) Tropicamide (1%): an effective cycloplegic agent for myopic children. Invest Ophthalmol Vis Sci 42(8): 1728–1735.
16.Yen MY, et al. (1989) Comparison of the effect of atropine and cyclopentolate on myopia. Ann Ophthalmol 21(5): 180–182, 187.
17.Quinn GE, et al. (1995) Association of intraocular pressure and myopia in children. Ophthalmology 102(2): 180–185.
18.Wiener M. (1931) The use of epinephrin in progressive myopia. Am J Ophthalmol 14: 520–522.
19.Chua WH, et al. (2006) Atropine for the treatment of childhood myopia. Ophthalmology 113(12): 2285–2291.
20.Tong L, et al. (2009) Atropine for the treatment of childhood myopia: effect on myopia progression after cessation of atropine. Ophthalmology 116(3): 572–579.
21.Barathi VA, Weon SR, Beuerman RW. (2009) Expression of muscarinic receptors in human and mouse sclera and their role in the regulation of scleral fibroblasts proliferation. Mol Vis 15: 1277–1293.
22.Liu S, et al. (2007) The eyelid margin: a transitional zone for 2 epithelial phenotypes. Arch Ophthalmol 125(4): 523–532.
358L.M.G. Tong, V.A. Barathi and R.W. Beuerman
23.McBrien NA, Gentle A. (2001) The role of visual information in the control of scleral matrix biology in myopia. Curr Eye Res 23(5): 313–319.
24.Wessler I, Kirkpatrick CJ. (2008) Acetylcholine beyond neurons: the non-neuronal cholinergic system in humans. Br J Pharmacol 154(8): 1558–1571.
25.Borda E, et al. (2005) Correlations between neuronal nitric oxide synthase and muscarinic M3/M1 receptors in the rat retina. Exp Eye Res 80(3): 391–399.
26.Collison DJ, et al. (2000) Characterization of muscarinic receptors in human lens cells by pharmacologic and molecular techniques. Invest Ophthalmol Vis Sci 41(9): 2633–2641.
27.Narayan S, et al. (2003) Endothelin-1 synthesis and secretion in human retinal pigment epithelial cells (ARPE-19): differential regulation by cholinergics and TNF-alpha. Invest Ophthalmol Vis Sci 44(11): 4885–4894.
28.Yin GC, Gentle A, McBrien NA. (2004) Muscarinic antagonist control of myopia: a molecular search for the M1 receptor in chick. Mol Vis 10: 787–793.
29.Bitzer M, et al. (2006) Effects of muscarinic antagonists on ZENK expression in the chicken retina. Exp Eye Res 82(3): 379–388.
30.Wessler I, Kirkpatrick CJ, Racke K. (1998) Non-neuronal acetylcholine, a locally acting molecule, widely distributed in biological systems: expression and function in humans. Pharmacol Ther 77(1): 59–79.
31.Gil DW, et al. (1997) Muscarinic receptor subtypes in human iris-ciliary body measured by immunoprecipitation. Invest Ophthalmol Vis Sci 38(7): 1434–1442.
32.Savinainen JR, Laitinen JT. (2004) Detection of cannabinoid CB1, adenosine A1, muscarinic acetylcholine, and GABA(B) receptor-dependent G protein activity in transducin-deactivated membranes and autoradiography sections of rat retina. Cell Mol Neurobiol 24(2): 243–256.
33.Qu J, et al. (2006) The presence of m1 to m5 receptors in human sclera: evidence of the sclera as a potential site of action for muscarinic receptor antagonists. Curr Eye Res 31(7–8): 587–597.
34.McBrien NA, et al. (2009) Expression of muscarinic receptor subtypes in tree shrew ocular tissues and their regulation during the development of myopia. Mol Vis 15: 464–475.
35.Liu Q, et al. (2007) Changes in muscarinic acetylcholine receptor expression in form deprivation myopia in guinea pigs. Mol Vis 13: 1234–1244.
36.Schwahn HN, Kaymak H, Schaeffel F. (2000) Effects of atropine on refractive development, dopamine release, and slow retinal potentials in the chick. Vis Neurosci 17(2): 165–176.
37.Taylor BJ, Smith PJ, Brook CG. (1985) Inhibition of physiological growth hormone secretion by atropine. Clin Endocrinol (Oxf) 22(4): 497–501.
38.Shih YF, et al. (1999) Effects of different concentrations of atropine on controlling myopia in myopic children. J Ocul Pharmacol Ther 15(1): 85–90.
359Atropine and Other Pharmacological Approaches to Prevent Myopia
39.Schwartz JT. (1981) Results of a monozygotic cotwin control study on a treatment for myopia. Prog Clin Biol Res 69: 249–258.
40.Sampson WG. (1979) Role of cycloplegia in the management of functional myopia. Ophthalmology 86(5): 695–697.
41.Chou AC, et al. (1997) The effectiveness of 0.5% atropine in controlling high myopia in children. J Ocul Pharmacol Ther 13(1): 61–67.
42.Jensen H. (1991) Myopia progression in young school children. A prospective study of myopia progression and the effect of a trial with bifocal lenses and beta blocker eye drops. Acta Ophthalmol Suppl 200: 1–79.
43.Shih YF, et al. (2001) An intervention trial on efficacy of atropine and multifocal glasses in controlling myopic progression. Acta Ophthalmol Scand 79(3): 233–236.
44.Liu H, et al. (1994) Treatment of adolescent myopia by pressure plaster of semen impatientis on otoacupoints. J Tradit Chin Med 14(4): 283–286.
45.Lucas JL, DeYoung JA, Sadee W. (2001) Single nucleotide polymorphisms of the human M1 muscarinic acetylcholine receptor gene. AAPS PharmSci 3(4): E31.
46.Boulesteix AL, et al. (2007) Multiple testing for SNP–SNP interactions. Stat Appl Genet Mol Biol 6: Article37.
47.Luu CD, et al. (2005) Multifocal electroretinogram in children on atropine treatment for myopia. Br J Ophthalmol 89(2): 151–153.
48.McBrien NA, Moghaddam HO, Reeder AP. (1993) Atropine reduces experimental myopia and eye enlargement via a nonaccommodative mechanism.
Invest Ophthalmol Vis Sci 34(1): 205–215.
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