The Role of Atropine in Preventing Myopia Progression: Comparison
Please note this is a comparison between versions V2 by Lindsay Dong and V1 by Lorenzo Ferro Desideri.

Myopia, also known as ‘nearsightedness’, is the one of the most common refractive diseases worldwide, and its prevalence is likely to rapidly increase in the near future.

  • myopia
  • atropine

1. Introduction

Myopia, also known as ‘nearsightedness’, is the one of the most common refractive diseases worldwide, and its prevalence is likely to rapidly increase in the near future [1,2][1][2]. Its onset usually occurs during childhood and it is caused by an excessive axial elongation of the eyes [3]. In some cases, myopia is a mere refractive error that can be corrected with spectacles, contact lenses, or refractive surgery. However, a smaller percentage of patients develop high myopia, which is currently defined by the World Health Organization (WHO) as a loss of six diopters (D) or greater. High myopia can lead to complications in the macula, in the peripheral retina, in the optic nerve, and in the lens and is therefore associated with an increased risk of blindness [4,5,6,7][4][5][6][7]. Moreover, myopic anisometropia may lead to amblyopia [8]. This shows the potential negative social and economic impact of myopia on healthcare systems all over the world.
Although we are still waiting for an evidence-based treatment algorithm for myopia, some strategies have shown a variable effectiveness in slowing its progression. These include more time spent outdoors [9[9][10],10], progressive addition lenses spectacles (PALs) [9[9][11][12],11,12], prismatic bifocal lenses spectacles (PBLs) [9[9][13],13], defocus spectacle lenses [14], soft contact lenses (SCLs) [9[9][15][16][17][18][19][20],15,16,17,18,19,20], orthokeratology (OK) [9[9][21][22][23][24][25][26][27][28][29][30],21,22,23,24,25,26,27,28,29,30], and various concentrations of antimuscarinic eye drops, mainly atropine, cyclopentolate, and pirenzepine [9]. These strategies are sometimes combined in order to increase their efficacy.
Time spent outdoors decreases the incidence of myopia in children, but its effect on the progression rate is insignificant [9,10][9][10]. PALs did not show a satisfactory efficacy [9,11,12][9][11][12]. PBLs led to a modest but significant decrease in axial elongation (AL) in myopic patients [9,13][9][13]. Of note, a significant reduction in myopia progression with minimal side effects was recently observed for defocus incorporated multiple segments (DIMS) spectacle lenses [14].
The results of OK have been encouraging in terms of clinical efficacy [21[21][22],22], but some concerns are represented by their possible drawbacks, including the risk of infectious keratitis and a relatively high dropout rate [23,24,25,26,27,28,29,30][23][24][25][26][27][28][29][30].
Finally, SCLs proved to have a modest efficacy in the slowing of myopia progression, albeit superior to spectacle lenses, especially for peripheral defocus modifying ones [9,15,16,17][9][15][16][17].
New developments in this field include MiSight contact lenses, whose efficacy was demonstrated in at least two clinical trials [18,31][18][31].
To date, atropine has shown promising results in preventing myopia progression. In particular, lower doses of atropine have revealed the most advantageous in balancing between clinical efficacy and the low rate of adverse effects, even though a rebound phenomenon after the interruption of the treatment has been reported [9]. Pirenzepine (an M1-selective antimuscarinic) and oral 7-methylxantine (an adenosine antagonist) have also been reported to slow myopia progression in children [32,33][32][33].

2. The Role of Atropine in Preventing Myopia Progression

2.1. Antimuscarinic Eye Drops: Overview of the Market

Antimuscarinic drops are used all over the world as cycloplegics, mydriatics, and for the penalization of the healthy eye in the treatment of amblyopia [34]. In the last decades, we have witnessed an increase of evidence proving the efficacy of antimuscarinic drugs in preventing myopia progression in children all over the world. However, their ocular topical use is still off-label in many countries. In fact, no pharmaceutical agent has been approved by the US FDA for preventing myopia progression, although atropine is already used in Asia to control myopia in children [35]. The effectiveness in preventing myopia progression in children has been demonstrated for different concentrations of atropine, cyclopentolate 1%, and for pirenzepine 2% [9]. Several randomized trials and meta-analyses have explored both the efficacy and the side effects of different atropine concentrations. The impact on AL and SED was highest for 1% atropine and lowest for 0.1% [35,36,37][35][36][37]. However, higher concentrations were also less tolerable and had a higher incidence of rebound effect after treatment discontinuation [34].

2.2. Atropine: Introduction to the Compound

Chemical formula The chemical formula of atropine is the following: C17H23NO3.

2.3. Pharmacokinetics

Topical atropine has a partition coefficient of 1.83 and a pKa of 9.43 at 7.4 pH, which means that it is ionized on the ocular surface [41,42][38][39]. A recent pharmacokinetic study on rabbits revealed that after 5 h from topical administration, the highest concentration of atropine was detected in the conjunctiva, with a concentration gradient established anteriorly to posteriorly. Moreover, the concentrations in the cornea and sclera were similar. Therefore, the authors concluded that atropine reaches the anterior and posterior chambers by simple diffusion via the conjunctival, scleral and uveal routes [43][40]. After 24 h, preferential binding of atropine to posterior ocular tissues was found. Atropine showed a good ocular bioavailability with concentrations of two magnitudes higher than its binding affinity in most tissues after 3 days [43][40]. It has been also reported that atropine binds melanin, both in vitro and in rabbits [44][41]. In humans, the systemic absorption of topically applied atropine is generally low, but systemic side effects can indeed occur, especially in children, likely due to their smaller body volumes. In one study the reported systemic bioavailability of atropine in healthy individuals ranged from 19% to 95% [45][42]. The largest amount of the drug is metabolized by enzymatic hydrolysis, particularly in the liver and 13–50% of the molecule is excreted unmodified in the urine [46,47][43][44]. Pharmacokinetic studies highlighted that the pharmacological effect begins after 48–120 min from its administration and lasts until 7–14 days [48][45].

2.4. Pharmacodynamics

Atropine is a nonselective reversible muscarinic antagonist. It binds to all five subtypes of muscarinic receptors (mAchR, MR1–MR5), preventing acetylcholine from interacting with them. On the other hand, pirenzepine is M1-selective [49,50][46][47]. These receptors are coupled with G-proteins (GPCR) and have been found in the human iris, ciliary body [51][48], lens epithelium [52][49], retinal amacrine [53][50] and pigment epithelial cells [54[51][52],55], and scleral fibroblasts [56][53]. The pathological mechanism of myopia and the pathways involved in the antimyopic effects of atropine are still largely unknown. However, some evidence on the matter does exist. For example, Lind et al. studied chick fibroblasts in vitro and reported that the antimyopic effect of antimuscarinics may be at least partially mediated by the inhibition of M1 receptors in the sclera [57][54]. A study in chicks demonstrated the inefficacy of M2 antagonists in opposing form deprivation myopia [58][55]. However, M2 receptors have been implicated in myopia development in an in vivo study on mice [59][56]. It was also reported that a M4-antagonist can prevent myopia progression in chicks [60][57]. Therefore, one of the pathways for the antimyopic effect of antimuscarinics is the interaction with ocular mAchR. In this regard, a protective role of dopamine (DA) has long been described [62][58], but a comprehensive theory for its mechanism of action is still lacking [63][59]. In the human retina, dopamine is produced by amacrine and interplexiform cells [64][60]. Dopamine has five GPCRs (D1–D5), some of which have been identified in animal retinal cells and RPE [65,66,67][61][62][63]. In mice, the activation of D1 inhibited the development of myopia [68,69][64][65]. In tree shrews, the activation of D2 and D4 receptors was reported to have an antimyopic effect [70][66], but in guinea pigs and D2 knock-out mice the activation of the D2 receptor seemed to do the opposite [71,72][67][68]. Moreover, nonselective D-agonists can inhibit myopia progression in animal models [73,74][69][70]. This leads us to the conclusion that atropine and DA could act in parallel biochemical pathways that would later converge on a common effector [75][71]. In particular, in preclinical models, atropine has been shown to stimulate the release of DA into the extracellular space and the vitreous, which may inhibit a retinal signaling process that is supposed to be involved in axial elongation, and thus myopia progression [76][72].

2.5. Clinical Efficacy

In the last few decades, low concentrations of atropine have gained considerable attention for their efficacy in slowing myopia progression in children. This was initially reported in non-randomized studies [86,87,88][73][74][75]. Subsequently, the Atropine for the Treatment of Childhood Myopia study (ATOM 1), which was a two-year long, randomized, placebo-controlled, double-masked trial, demonstrated that the progression of myopia was substantially slower in the group treated with atropine 1% than in the one that received a placebo. Specifically, 65.7% of atropine-treated eyes had a progression of less than 0.50 D, and 13.9% of them progressed more than 1.00 D. In contrast, 16.1% and 63.9% of placebo-treated eyes showed a progression of less than 0.50 D and more than 1.00 D, respectively [35]. Moreover, after two years, the treated group had a significantly slower myopia progression, with a difference of −0.92 D in SED (95% confidence interval (CI): −1.10 to −0.77 D; p < 0.001) and 0.40 mm in AL (95% CI: 0.35–0.45 mm; p < 0.001) compared with the placebo. Subsequently, the Atropine for the Treatment of Childhood Myopia 2 (ATOM 2) study was published, which had the aim to assess whether lower concentrations of atropine could be effective in reducing myopia progression, with potentially fewer side effects. The study comprised a two year-long treatment phase, followed by a one-year-long washout period. Patients were randomized into three treatment groups (atropine 0.5%, atropine 0.1% and atropine 0.01%). After two years, myopia progression was lowest in the group treated with atropine 0.5% and highest in the 0.01% one. However, the progression rate of patients treated with atropine 0.01% was deemed clinically not very different from that seen at higher concentrations, and the ocular side effect profile was significantly better. Indeed, 50% of the 0.01% group progressed by less than 0.5 D, while these rates were 58% and 63% in the 0.1% and 0.5% groups, respectively. Among all three groups, around 18% of subjects progressed by 1.0 D or more [91][76].

3.6. Safety and Tolerability

Topical atropine is associated with some ocular AEs, including mydriasis, photophobia, and reduced accommodation, with symptoms of glare and blur during near-work activities. Although usually mild, side effects can hinder school and outdoor activities, and therefore represent a significant cause of treatment interruption. The most problematic AEs reported with atropine eye drops are the rebound phenomenon and ocular side effects, which occur in around 5% of patients. The former is defined as the rapid increase in axial elongation shortly after treatment discontinuation. Other relevant side effects are an ocular allergic reaction and photophobia and blurriness of near vision, which are due to myosis and cycloplegia [35,37,94,98,99][35][37][77][78][79]. The ocular side effects are more common and marked at higher concentrations of the molecule. This is especially true for the rebound phenomenon, which seems to be dose-related. In addition to this, low concentrations of atropine are often available in formulations that use benzalkonium chloride (BAK) as a preservative, which is known to be toxic to the corneal epithelium and it has been associated with dry eye syndrome. Some studies have even highlighted its toxic effects to the retinal tissue [101,102][80][81]. The ATOM 1 study reported only ocular side effects, which were allergic reactions (4.5%), glare (1.5%) and blurred near vision (1%) [35]. During the ATOM 2 study, the rebound phenomenon appeared to be dose-related [36].

3. Conclusions

Atropine has been long known for its properties as a mydriatic and cycloplegic. Recently, a new side to this molecule has emerged, which is its potential in preventing myopia progression in children and adolescents [35,36,37][35][36][37]. However, the exact mechanism of action of this drug and the pathophysiology of myopia onset and progression remain to be clarified. In any case, atropine has shown promise in preventing the progression of myopia in children, and we are constantly transitioning to a concentration that has the highest efficacy and fewest side effects. Indeed, despite being more effective, higher concentrations (1%, 0.5%) are associated with an increased risk of a rebound phenomenon and ocular side effects [35,36][35][36]. On the other hand, lower concentrations (in particular 0.05%) seem to maintain a clinically satisfying efficacy, with a much lower incidence of ocular side effects [9,37][9][37]. As a consequence, low concentrations of atropine appear to have a better clinical profile and represent a valid treatment strategy to slow the progression of myopia in children and adolescents. However, further randomized clinical trials with larger follow-up periods are needed.

References

  1. Dolgin, E. The myopia boom. Nature 2015, 519, 276–278.
  2. Delcourt, C.; Korobelnik, J.-F.; Buitendijk, G.H.S.; Foster, P.; Hammond, C.; Piermarocchi, S.; Peto, T.; Jansonius, N.; Mirshahi, A.; Hogg, R.; et al. Ophthalmic epidemiology in Europe: The “European Eye Epidemiology” (E3) consortium. Eur. J. Epidemiol. 2015, 31, 197–210.
  3. Fledelius, H.C. Ophthalmic changes from age of 10 to 18 years. Acta Ophthalmol. 2009, 60, 403–411.
  4. Kocur, I.; Resnikoff, S.; Naidoo, K.S. Impact of Myopia Impact of Increasing and Myopia. No. July 2017, 2015. Available online: https://www.researchgate.net/publication/318216691_The_impact_of_myopia_and_high_myopia_Report_of_the_Joint_World_Health_Organization-Brien_Holden_Vision_Institute_Global_Scientific_Meeting_on_Myopia (accessed on 21 March 2022).
  5. Verhoeven, V.J.; Wong, K.T.; Buitendijk, G.H.; Hofman, A.; Vingerling, J.R.; Klaver, C.C. Visual Consequences of Refractive Errors in the General Population. Ophthalmology 2015, 122, 101–109.
  6. Pellegrini, M.; Vagge, A.; Desideri, L.F.F.; Bernabei, F.; Triolo, G.; Mastropasqua, R.; Del Del Noce, C.; Borrelli, E.; Sacconi, R.; Iovino, C.; et al. Optical Coherence Tomography Angiography in Neurodegenerative Disorders. J. Clin. Med. 2020, 9, 1706.
  7. Li, M.; Yang, Y.; Jiang, H.; Gregori, G.; Roisman, L.; Zheng, F.; Ke, B.; Qu, D.; Wang, J. Retinal Microvascular Network and Microcirculation Assessments in High Myopia. Am. J. Ophthalmol. 2016, 174, 56–67.
  8. Gawęcki, M. Threshold Values of Myopic Anisometropia Causing Loss of Stereopsis. J. Ophthalmol. 2019, 2019, 2654170.
  9. Huang, J.; Wen, D.; Wang, Q.; McAlinden, C.; Flitcroft, I.; Chen, H.; Saw, S.M.; Chen, H.; Bao, F.; Zhao, Y.; et al. Efficacy Comparison of 16 Interventions for Myopia Control in Children. Ophthalmology 2016, 123, 697–708.
  10. Xiong, S.; Sankaridurg, P.; Naduvilath, T.; Zang, J.; Zou, H.; Zhu, J.; Lv, M.; He, X.; Xu, X. Time spent in outdoor activities in relation to myopia prevention and control: A meta-analysis and systematic review. Acta Ophthalmol. 2017, 95, 551–566.
  11. Hyman, L.; Gwiazda, J.; Marsh-Tootle, W.L.; Norton, T.T.; Hussein, M. The Correction of Myopia Evaluation Trial (COMET): Design and General Baseline Characteristics. Control. Clin. Trials 2001, 22, 573–592.
  12. Correction of Myopia Evaluation Trial 2 Study Group for the Pediatric Eye Disease Investigator Group. Progressive-Addition Lenses versus Single-Vision Lenses for Slowing Progression of Myopia in Children with High Accommodative Lag and Near Esophoria. Investig. Ophthalmol. Vis. Sci. 2011, 52, 2749–2757.
  13. Cheng, D.; Woo, G.C.; Drobe, B.; Schmid, K. Effect of Bifocal and Prismatic Bifocal Spectacles on Myopia Progression in Children. JAMA Ophthalmol. 2014, 132, 258–264.
  14. Lam, C.S.Y.; Tang, W.C.; Tse, D.Y.-Y.; Lee, R.P.K.; Chun, R.K.M.; Hasegawa, K.; Qi, H.; Hatanaka, T.; To, C.H. Defocus Incorporated Multiple Segments (DIMS) spectacle lenses slow myopia progression: A 2-year randomised clinical trial. Br. J. Ophthalmol. 2019, 104, 363–368.
  15. Aller, T.A.; Liu, M.; Wildsoet, C.F. Myopia Control with Bifocal Contact Lenses. Optom. Vis. Sci. 2016, 93, 344–352.
  16. Jessen, G.N. World wide summary of contact lens techniques. Optom. Vis. Sci. 1962, 39, 680–682.
  17. Katz, J.; Schein, O.D.; Levy, B.; Cruiscullo, T.; Saw, S.-M.; Rajan, U.; Chan, T.-K.; Khoo, C.Y.; Chew, S.-J. A randomized trial of rigid gas permeable contact lenses to reduce progression of children’s myopia. Am. J. Ophthalmol. 2003, 136, 82–90.
  18. Chamberlain, P.; Peixoto-De-Matos, S.C.; Logan, N.S.; Ngo, C.; Jones, D.; Young, G. A 3-year Randomized Clinical Trial of MiSight Lenses for Myopia Control. Optom. Vis. Sci. 2019, 96, 556–567.
  19. Ruiz-Pomeda, A.; Prieto-Garrido, F.L.; Verdejo, J.L.H.; Villa-Collar, C. Rebound Effect in the Misight Assessment Study Spain (Mass). Curr. Eye Res. 2021, 46, 1223–1226.
  20. Lam, C.S.Y.; Tang, W.C.; Tse, D.Y.-Y.; Tang, Y.Y.; To, C.-H. Defocus Incorporated Soft Contact (DISC) lens slows myopia progression in Hong Kong Chinese schoolchildren: A 2-year randomised clinical trial. Br. J. Ophthalmol. 2013, 98, 40–45.
  21. Cho, P.; Cheung, S.W.; Edwards, M. The Longitudinal Orthokeratology Research in Children (LORIC) in Hong Kong: A Pilot Study on Refractive Changes and Myopic Control. Curr. Eye Res. 2005, 30, 71–80.
  22. Cho, P.; Cheung, S.-W.; Shah, N.; Dakin, S.C.; Anderson, R.S. Retardation of Myopia in Orthokeratology (ROMIO) Study: A 2-Year Randomized Clinical Trial. Investig. Ophthalmol. Vis. Sci. 2012, 53, 7077–7085.
  23. Hsiao, C.-H.; Lin, H.-C.; Chen, Y.-F.; Ma, D.H.K.; Yeh, L.-K.; Tan, H.-Y.; Huang, S.C.M.; Lin, K.-K. Infectious Keratitis Related to Overnight Orthokeratology. Cornea 2005, 24, 783–788.
  24. Chan, T.; Li, E.Y.; Wong, V.W.Y.; Jhanji, V. Orthokeratology-Associated Infectious Keratitis in a Tertiary Care Eye Hospital in Hong Kong. Am. J. Ophthalmol. 2014, 158, 1130–1135.e2.
  25. Hutchinson, K.; Apel, A. Infectious keratitis in orthokeratology. Clin. Exp. Ophthalmol. 2002, 30, 49–51.
  26. Sun, X.; Zhao, H.; Deng, S.; Zhang, Y.; Wang, Z.; Li, R.; Luo, S.; Jin, X. Infectious keratitis related to orthokeratology. Ophthalmic Physiol. Opt. 2006, 26, 133–136.
  27. Wilhelmus, K.R. Acanthamoeba Keratitis During Orthokeratology. Cornea 2005, 24, 864–866.
  28. Shehadeh-Masha’Our, R.; Segev, F.; Barequet, I.; Ton, Y.; Garzozi, H. Orthokeratology Associated Microbial Keratitis. Eur. J. Ophthalmol. 2009, 19, 133–136.
  29. Walline, J.J.; Jones, L.A.; Sinnott, L.T. Corneal reshaping and myopia progression. Br. J. Ophthalmol. 2009, 93, 1181–1185.
  30. Santodomingo-Rubido, J.; Villa-Collar, C.; Gilmartin, B.; Gutiérrez-Ortega, R. Myopia Control with Orthokeratology Contact Lenses in Spain: Refractive and Biometric Changes. Investig. Opthalmol. Vis. Sci. 2012, 53, 5060–5065.
  31. Ruiz-Pomeda, A.; Pérez-Sánchez, B.; Valls, I.; Garrido, F.L.P.; Gutierrez, R.; Villa-Collar, C. MiSight Assessment Study Spain (MASS). A 2-year randomized clinical trial. Graefe’s Arch. Clin. Exp. Ophthalmol. 2018, 256, 1011–1021.
  32. Siatkowski, R.M.; Cotter, S.A.; Crockett, R.; Miller, J.M.; Novack, G.; Zadnik, K. Two-year multicenter, randomized, double-masked, placebo-controlled, parallel safety and efficacy study of 2%pirenzepineophthalmicgelinchildrenwithmyopia. J. Am. Assoc. Pediatr. Ophthalmol. Strabismus 2008, 12, 332–339.
  33. Trier, K.; Ribel-Madsen, S.; Cui, D.; Christensen, S.B. Systemic 7-methylxanthine in retarding axial eye growth and myopia progression: A 36-month pilot study. J. Ocul. Biol. Dis. Inform. 2008, 1, 85–93.
  34. Vagge, A.; Desideri, L.F.; Traverso, C.E. An update on pharmacological treatment options for amblyopia. Int. Ophthalmol. 2020, 40, 3591–3597.
  35. Chua, W.-H.; Balakrishnan, V.; Chan, Y.-H.; Tong, L.; Ling, Y.; Quah, B.-L.; Tan, D. Atropine for the Treatment of Childhood Myopia. Ophthalmology 2006, 113, 2285–2291.
  36. Chia, A.; Chua, W.-H.; Cheung, Y.-B.; Wong, W.-L.; Lingham, A.; Fong, A.; Tan, D. Atropine for the Treatment of Childhood Myopia: Safety and Efficacy of 0.5%, 0.1%, and 0.01% Doses (Atropine for the Treatment of Myopia 2). Ophthalmology 2012, 119, 347–354.
  37. Yam, J.C.; Li, F.F.; Zhang, X.; Tang, S.M.; Yip, B.H.; Kam, K.W.; Ko, S.T.; Young, A.L.; Tham, C.C.; Chen, L.J.; et al. Two-Year Clinical Trial of the Low-Concentration Atropine for Myopia Progression (LAMP) Study. Ophthalmology 2020, 127, 910–919.
  38. Exploring QSAR: Hydrophobic, Electronic, and Steric Constants; American Chemical Society: Washington, DC, USA, 1995; Volume 2.
  39. Sangster, J. LOGKOW Databank. 1994.
  40. Wang, L.Z.; Syn, N.; Li, S.; Barathi, V.A.; Tong, L.; Neo, J.; Beuerman, R.W.; Zhou, L. The penetration and distribution of topical atropine in animal ocular tissues. Acta Ophthalmol. 2018, 97, e238–e247.
  41. Atlasik, B.; Stepien, K.; Wilczok, T. Interaction of drugs with ocular melanin in vitro. Exp. Eye Res. 1980, 30, 325–331.
  42. Kaila, T.; Korte, J.-M.; Saari, K.M. Systemic bioavailability of ocularly applied 1% atropine eyedrops. Acta Ophthalmol. Scand. 1999, 77, 193–196.
  43. van der Meer, M.J.; Hundt, H.K.L.; Müller, F.O. The metabolism or atropine in man. J. Pharm. Pharmacol. 1986, 38, 781–784.
  44. Janes, R.G. The Penetration of C14-Labeled Atropine into the Eye. A.M.A. Arch. Ophthalmol. 1959, 62, 69–74.
  45. Basic and Clinical Science Course, Section 02: Fundamentals and Principles of Ophthalmology; American Academy of Ophthalmology: San Francisco, CA, USA, 2021; ISBN 978-1-68104-466-8.
  46. Dörje, F.; Wess, J.; Lambrecht, G.; Tacke, R.; Mutschler, E.; Brann, M.R. Antagonist binding profiles of five cloned human muscarinic receptor subtypes. J. Pharmacol. Exp. Ther. 1991, 256, 727–733.
  47. Buckley, N.J.; Bonner, T.I.; Buckley, C.M.; Brann, M.R. Antagonist binding properties of five cloned muscarinic receptors expressed in CHO-K1 cells. Mol. Pharmacol. 1989, 35, 469–476.
  48. Gil, D.W.; Krauss, H.A.; Bogardus, A.M.; WoldeMussie, E. Muscarinic receptor subtypes in human iris-ciliary body measured by immunoprecipitation. Investig. Ophthalmol. Vis. Sci. 1997, 38, 1434–1442.
  49. Collison, D.J.; Coleman, R.A.; James, R.S.; Carey, J.; Duncan, G. Characterization of muscarinic receptors in human lens cells by pharmacologic and molecular techniques. Investig. Ophthalmol. Vis. Sci. 2000, 41, 2633–2641.
  50. Gleason, E. The influences of metabotropic receptor activation on cellular signaling and synaptic function in amacrine cells. Vis. Neurosci. 2011, 29, 31–39.
  51. Friedman, Z.; Hackett, S.F.; Campochiaro, P.A. Human retinal pigment epithelial cells possess muscarinic receptors coupled to calcium mobilization. Brain Res. 1988, 446, 11–16.
  52. Ruan, Y.; Patzak, A.; Pfeiffer, N.; Gericke, A. Muscarinic Acetylcholine Receptors in the Retina—Therapeutic Implications. Int. J. Mol. Sci. 2021, 22, 4989.
  53. Barathi, V.A.; Weon, S.R.; Beuerman, R.W. Expression of muscarinic receptors in human and mouse sclera and their role in the regulation of scleral fibroblasts proliferation. Mol. Vis. 2009, 15, 1277–1293.
  54. Lind, G.J.; Chew, S.J.; Marzani, D.; Wallman, J. Muscarinic acetylcholine receptor antagonists inhibit chick scleral chondrocytes. Investig. Ophthalmol. Vis. Sci. 1998, 39, 2217–2231.
  55. Stone, R.A.; Lin, T.; Laties, A.M. Muscarinic antagonist effects on experimental chick myopia. Exp. Eye Res. 1991, 52, 755–758.
  56. Barathi, V.A.; Kwan, J.L.; Tan, Q.S.W.; Weon, S.R.; Seet, L.F.; Goh, L.K.; Vithana, E.N.; Beuerman, R.W. Muscarinic cholinergic receptor (M2) plays a crucial role in the development of myopia in mice. Dis. Model. Mech. 2013, 6, 1146–1158.
  57. McBrien, N.A.; Arumugam, B.; Gentle, A.; Chow, A.; Sahebjada, S. The M4 muscarinic antagonist MT-3 inhibits myopia in chick: Evidence for site of action. Ophthalmic Physiol. Opt. 2011, 31, 529–539.
  58. Stone, R.A.; Lin, T.; Laties, A.M.; Iuvone, P.M. Retinal dopamine and form-deprivation myopia. Proc. Natl. Acad. Sci. USA 1989, 86, 704–706.
  59. Zhou, X.; Pardue, M.T.; Iuvone, P.M.; Qu, J. Dopamine signaling and myopia development: What are the key challenges. Prog. Retin. Eye Res. 2017, 61, 60–71.
  60. Frederick, J.M.; Rayborn, M.E.; Laties, A.M.; Lam, D.M.K.; Hollyfield, J.G. Dopaminergic neurons in the human retina. J. Comp. Neurol. 1982, 210, 65–79.
  61. Veruki, M.L.; Wässle, H. Immunohistochemical Localization of Dopamine D Receptors in Rat Retina. Eur. J. Neurosci. 1996, 8, 2286–2297.
  62. Versaux-Botteri, C.; Gibert, J.-M.; Nguyen-Legros, J.; Vernier, P. Molecular identification of a dopamine D1b receptor in bovine retinal pigment epithelium. Neurosci. Lett. 1997, 237, 9–12.
  63. Rohrer, B.; Stell, W.K. Localization of putative dopamine D2-like receptors in the chick retina, using in situ hybridization and immunocytochemistry. Brain Res. 1995, 695, 110–116.
  64. Zhou, X.; Xiong, W.; Huang, F.; Yang, J.; Qu, J. C57BL/6 mouse eyes treated by dopamine D1 receptor agonist and antagonist during form deprivation: An opposite effect on axial length and refractive development. Investig. Ophthalmol. Vis. Sci. 2014, 55, 3038.
  65. Chen, S.; Zhi, Z.; Ruan, Q.; Liu, Q.; Li, F.; Wan, F.; Reinach, P.S.; Chen, J.; Qu, J.; Zhou, X. Bright Light Suppresses Form-Deprivation Myopia Development With Activation of Dopamine D1 Receptor Signaling in the ON Pathway in Retina. Investig. Opthalmol. Vis. Sci. 2017, 58, 2306–2316.
  66. Ward, A.H.; Siegwart, J.T.; Frost, M.R.; Norton, T.T. Intravitreally-administered dopamine D2-like (and D4), but not D1-like, receptor agonists reduce form-deprivation myopia in tree shrews. Vis. Neurosci. 2017, 34, E003.
  67. Zhang, S.; Yang, J.; Reinach, P.S.; Wang, F.; Zhang, L.; Fan, M.; Ying, H.; Pan, M.; Qu, J.; Zhou, X. Dopamine Receptor Subtypes Mediate Opposing Effects on Form Deprivation Myopia in Pigmented Guinea Pigs. Investig. Ophthalmol. Vis. Sci. 2018, 59, 4441–4448.
  68. Huang, F.; Yan, T.; Shi, F.; An, J.; Xie, R.; Zheng, F.; Li, Y.; Chen, J.; Qu, J.; Zhou, X. Activation of Dopamine D2 Receptor Is Critical for the Development of Form-Deprivation Myopia in the C57BL/6 Mouse. Investig. Ophthalmol. Vis. Sci. 2014, 55, 5537–5544.
  69. Iuvone, P.M.; Tigges, M.; Stone, R.A.; Lambert, S.; Laties, A.M. Effects of apomorphine, a dopamine receptor agonist, on ocular refraction and axial elongation in a primate model of myopia. Investig. Ophthalmol. Vis. Sci. 1991, 32, 1674–1677.
  70. Jiang, L.; Long, K.; Schaeffel, F.; Zhou, X.; Zheng, Y.; Ying, H.; Lu, F.; Stell, W.K.; Qu, J. Effects of Dopaminergic Agents on Progression of Naturally Occurring Myopia in Albino Guinea Pigs (Cavia porcellus). Investig. Opthalmol. Vis. Sci. 2014, 55, 7508–7519.
  71. Schmid, K.L.; Wildsoet, C.F. Inhibitory Effects of Apomorphine and Atropine and Their Combination on Myopia in Chicks. Optom. Vis. Sci. 2004, 81, 137–147.
  72. Schwahn, H.N.; Kaymak, H.; Schaeffel, F. Effects of atropine on refractive development, dopamine release, and slow retinal potentials in the chick. Vis. Neurosci. 2000, 17, 165–176.
  73. Bedrossian, R.H. The Effect of Atropine on Myopia. Ophthalmology 1979, 86, 713–717.
  74. Brodstein, R.S.; Brodstein, D.E.; Olson, R.J.; Hunt, S.C.; Williams, R.R. The Treatment of Myopia with Atropine and Bifocals. Ophthalmology 1984, 91, 1373–1378.
  75. Chou, A.-C.; Shih, Y.-F.; Ho, T.-C.; Lin, L.L.-K. The Effectiveness of 0.5% Atropine in Controlling High Myopia in Children. J. Ocul. Pharmacol. Ther. 1997, 13, 61–67.
  76. Chia, A.; Lu, Q.-S.; Tan, D. Five-Year Clinical Trial on Atropine for the Treatment of Myopia 2. Ophthalmology 2015, 123, 391–399.
  77. Polling, J.R.; Tan, E.; Driessen, S.; Loudon, S.E.; Wong, H.-L.; van der Schans, A.; Tideman, J.W.L.; Klaver, C.C.W. A 3-year follow-up study of atropine treatment for progressive myopia in Europeans. Eye 2020, 34, 2020–2028.
  78. Zhu, Q.; Tang, Y.; Guo, L.; Tighe, S.; Zhou, Y.; Zhang, X.; Zhang, J.; Zhu, Y.; Hu, M. Efficacy and Safety of 1% Atropine on Retardation of Moderate Myopia Progression in Chinese School Children. Int. J. Med. Sci. 2020, 17, 176–181.
  79. Diaz-Llopis, M.; Pinazo-Duran, M.D. La atropina superdiluida al 0.01% frena el aumento de miopía en niños-adolescentes. Un estudio a largo plazo 5 años de evolución: Seguridad y eficacia. Arch. Soc. Española Oftalmol. 2018, 93, 182–185.
  80. Baudouin, C.; Labbé, A.; Liang, H.; Pauly, A.; Brignole-Baudouin, F. Preservatives in eyedrops: The good, the bad and the ugly. Prog. Retin. Eye Res. 2010, 29, 312–334.
  81. Datta, S.; Baudouin, C.; Brignole-Baudouin, F.; Denoyer, A.; Cortopassi, G.A. The Eye Drop Preservative Benzalkonium Chloride Potently Induces Mitochondrial Dysfunction and Preferentially Affects LHON Mutant Cells. Investig. Ophthalmol. Vis. Sci. 2017, 58, 2406–2412.
More
Top
Feedback