1. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu Pharmacological Aspects of Myopia Christine Wildsoet University of California Berkeley Myopia: Strategies for the 21st Century Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu

2. Pharmacological intervention - not a very new idea Bedrossian atropine study (1966)  Underlying assumption  Excessive near work involved  Excessive accommodation implicated

3. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu Bedrossian (1966) Study  1% atropine nightly  age 7-13 yr  progressing myopes  refractions only Swap over time Incr. progression

4. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu Pharmacological intervention - options for treatment  Determining factors  Is myopia genetic &/or nonvisual?  Are visual factors involved? Scleral target Retinal (& higher level) target Animal models

5. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu Animal models Lesson from Bedrossian : Measure eye length + refractive errors

6. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu Drug options - Results from experimental studies & clinical trials  Main focus of studies  Dopaminergic agonists  Antimuscarinic drugs  Recent focus of attention  Nicotinic drugs  NO analogs  Retinoic acid  Glucagonergic analogs  GABA analogs Others studied  bFGF  TNF-   VIP  Melatonin  Enkephalins Retina - target for many studies!

7. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu Issues to consider in animal-based drug studies  Form deprivation myopia paradigm mostly commonly used  Form deprivation myopia & lens-induced myopia may involve different mechanisms  Intravitreal injection most common route of adminstration Relevance of studies to human myopia?

8. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu The retina as a drug target Many transmitters, many drug options! Amacrine cells & their transmitters of particular interest

9. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu DA analogs - First to be tested with animal models  Rationale  DA regulates retinal coupling  DA influences retinal spatial processing Low retinal DA High retinal DA

10. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu Dopamine analogs - Summary of observed effects  dopamine agonists inhibit myopia development  chick  monkey Key work in this area Stone, Laties & Tigges (chicks & monkeys) Schaeffel lab (chicks) Stell lab (chicks) Wildsoet & Schmid (chicks) Seko (chicks)

11. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu DA analogs - The earliest study? Chicks & form deprivation myopia Stone et al. Proc Nat Acad Sci (1989)

12. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu Apomorphine & chicks Effects on lens-induced myopia Schmid & Wildsoet ARVO (1998) -15 D lenses: worn from 8 days for 4 days

13. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu Apomorphine, FDM & monkeys Tigges et al. Invest Ophthalmol Vis Sci (1991) Form deprived (FD) 5-8 months with opaque contact lenses

14. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu Apomorphine, RPE & scleral growth in chick Seko et al. Cell, Biochemistry & Function (1997) Retinal pigment epitheium cultured with scleral chondrocytes +/- apomorphine

15. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu Dopaminergic effects - Some apparent inconsistencies  dopamine turnover decreases in FDM & LIM BUT  dopamine antagonists can also inhibit eye growth  agonists+antagonists enhance myopia  6-OHDA inhibits FDM, not LIM  reserpine inhibits both FDM & LIM FDM: form deprivation myopia LIM: lens induced myopia

16. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu Antimuscarinic drugs - Summary of observed effects  Antimuscarinic drugs inhibit myopia development  chicks  tree shrews  monkeys  humans Key work in this area Stone, Laties & Tigges (chicks/monkeys) Schaeffel lab (chicks) McBrien lab (chicks & tree shrews) Wildsoet & Schmid (chicks) Wallman lab (chicks) Shih (chicks) SERI (chicks)

17. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu Antimuscarinic drugs - Important insight from chick Ach receptors on chick ciliary muscles are nicotinic! Ciliary muscle is not the site of action Accommodation not the target!

18. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu Antimuscarinic drugs - the earliest chick study Stone et al. Exp Eye Res (1991) Lid suture for 2 weeks + daily SC injections Atropine (Atr, nonselective) Pirenzepine (Pir; M 1 ) Methoctramine (Met; M 2 ) 4-DAMP (DAMP, M 3 ) Increasing dose

19. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu M 4 -selective antimuscarinic drugs also work! Cottriall et al. NeuroReport (2001) Chicks were form deprived & treated with himbacine, a M 4 selective agent

20. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu Atropine & lens-induced myopia in chicks Wildsoet, McBrien & Clark ARVO (1994) Intravitreal injections 25 ug atropine every other day; measured after 7 days

21. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu Antimuscarinic drugs - They also work in mammals & primates Tigges et al. Optom Vis Sci (1999) Monkey

22. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu DA analogs + antimuscarinic drugs Can they be combined to improve efficacy? Schmid & Wildsoet Proc Aust Neurosci Soc (2000) Chicks: treated from day 8 - day 12

23. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu DA - Ach analog interactions Another perspective from DFP Cottriall & McBrien NS Arch Pharm (2001) Chicks form deprived & injected i.vit. with 2 ug DFP every other day +/-DA antagonists

24. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu Retinally-active drugs - Other possibilities  Nicotinic analogs  NOS inhibitors

25. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu Nicotinic analogs & myopia in chicks Stone et al. Invest Ophthalmol Vis Sci (2001) Chicks form-deprived CHL: chlorisondamine MEC: mecamylamine MLA: methyllcaconitine DHBE: dihyrdo-  -erythroidine

26. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu Nitric oxide analogs - Inhibition via a retinal pathway? Fujikado et al. Ophthalmic Res (2001) Chicks treated with 180 mM l-NAME & -16 D lens (significant effects observed at doses>60 mM) l-NAME inhibits oscillatory potentials

27. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu Retinally-active drugs “work” They tell us about mechanisms BUT How safe is the retina as a site of action for myopia control?

28. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu The neglected targets - IOP, scleral growth & ocular rhythms Targeted drugs  timolol  latanoprost  melatonin

29. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu IOP, timolol & myopia control in chicks -15 D lensDiffusers IOP decrease 8-10%, FDM; 13-14% LIM Schmid et al. Exp Eye Res (2001)

30. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu Latanoprost & myopia inhibition in chicks - Effect via IOP (or PGs)? Jin & Stjernschantz Acta Ophthalmol Scand (2000) Form-deprived for 1 week BID X2, separated by 3 days

31. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu The sclera - An alternative site of action for myopia control drugs? Curtin, 1985

32. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu  -xyloside study Inhibition PG synthesis in chicks Rada et al. Exp Eye Res (2002)

33. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu The sclera - An alternative site of action for antimuscarinic drugs?  Evidence  ECMA lesions  cell culture

34. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu ECMA lesions, atropine & myopia in chicks Fischer et al. Brain Res (1998) Chicks treated with 25 nmol ECMA, +/- form deprivation & 40 ug atropine daily for 6 days

35. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu Scleral cell culture & myopia in chicks Lind et al. Invest Ophthal Vis Sci (1998) Sulfate incorporation by chondrocytes Atr: atropine Pir: Pirenzepine DAMP: 4-DAMP Thymidine incorporation

36. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu So what about humans?

37. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu Timolol - Not effective for human myopia control! Jensen Acta Ophthalmologica (1991) 0.25% timolol, BID

38. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu Atropine & human myopia Recent findings are promising! Shih et al. Acta Ophthalmol Scand (2001) Refraction changes over 18 months - 0.25% atropine + multifocals cf. multifocal & single vision spectacles

39. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu Pirenzepine & human myopia Rumor has it that results from on-going trials are very promising!

40. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu But is it just that simple?

41. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu  Required treatment is very long term  chronically applied topical drugs cause ocular surface disease &/or allergies  chronically applied drugs cause tolerance  Target group is young  a retinal target site carries inherent risks  Questions to consider  Is there a better (safer) site - Yes, sclera?  Are there alternative routes of administration?  Are there other nonclassical drug options? Myopia control treatment - There are significant unresolved issues

42. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu Is oral administration a possibility? Pirenzepine works in chicks Flitcroft, Troilo & Wildsoet 8th International Myopia Meeting (2000)

43. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu Other drug options - Retinoic acid & effects on eye growth Mertz & Wallman Exp Eye Res (2001) Chick scleral punches assayed in culture

44. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu Antisense drugs & eye growth control in chicks McGuire & Stell ( 2000) Control2hr treated Fos-labelling AODN: antisense oligodeoxynucleotide

45. Christine Wildsoet, OD, PhD UC Berkeley Optometry vision.berkeley.edu/VSP/CW wildsoet@spectacle.berkeley.edu Drugs for myopia control The best way forward?