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Pharmacological Aspects of Myopia

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

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Pharmacological Aspects of Myopia

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  1. Myopia: Strategies for the 21st Century Pharmacological Aspects of Myopia Christine Wildsoet University of California Berkeley 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. Bedrossian (1966) Study • 1% atropine nightly • age 7-13 yr • progressing myopes • refractions only Swap overtime Incr. progression

  4. Pharmacological intervention - options for treatment • Determining factors • Is myopia genetic &/or nonvisual? • Are visual factors involved? Scleral target Animal models Retinal (& higher level)target

  5. Animal models Lesson from Bedrossian: Measure eye length + refractive errors

  6. Drug options - Results fromexperimental 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-b • VIP • Melatonin • Enkephalins Retina - target for many studies!

  7. 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. The retina as a drug targetMany transmitters, many drug options! Amacrine cells & their transmitters of particular interest

  9. DA analogs -First to be tested with animal models Low retinal DA • Rationale • DA regulates retinal coupling • DA influences retinal spatial processing High retinal DA

  10. 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. DA analogs - The earliest study?Chicks & form deprivation myopia Stone et al. Proc Nat Acad Sci (1989)

  12. Apomorphine & chicks Effects on lens-induced myopia -15 D lenses: worn from 8 days for 4 days Schmid & Wildsoet ARVO (1998)

  13. Apomorphine, FDM & monkeys Form deprived (FD) 5-8 monthswith opaque contact lenses Tigges et al. Invest Ophthalmol Vis Sci (1991)

  14. Apomorphine, RPE & scleral growth in chick Retinal pigment epitheium cultured with scleral chondrocytes +/- apomorphine Seko et al. Cell, Biochemistry & Function (1997)

  15. 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. 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. Antimuscarinic drugs - Important insight from chick Ach receptors on chick ciliary musclesare nicotinic! Ciliary muscle is not the site of action Accommodation not the target!

  18. Antimuscarinic drugs -the earliest chick study Increasing dose Lid suture for 2 weeks + daily SC injections Atropine (Atr, nonselective) Pirenzepine (Pir; M1) Methoctramine (Met; M2) 4-DAMP (DAMP, M3) Stone et al. Exp Eye Res (1991)

  19. M4-selective antimuscarinic drugs also work! Chicks were form deprived & treated with himbacine, a M4 selective agent Cottriall et al. NeuroReport (2001)

  20. Atropine & lens-induced myopia in chicks Intravitreal injections 25 ug atropine every other day; measured after 7 days Wildsoet, McBrien & Clark ARVO (1994)

  21. Antimuscarinic drugs - They also work in mammals & primates Monkey Tigges et al. Optom Vis Sci (1999)

  22. DA analogs + antimuscarinic drugsCan they be combined to improve efficacy? Chicks: treated from day 8 - day 12 Schmid & WildsoetProc Aust Neurosci Soc (2000)

  23. DA - Ach analog interactions Another perspective from DFP Chicks form deprived & injected i.vit. with 2 ug DFP every other day +/-DA antagonists Cottriall & McBrien NS Arch Pharm (2001)

  24. Retinally-active drugs -Other possibilities • Nicotinic analogs • NOS inhibitors

  25. Nicotinic analogs & myopia in chicks Chicks form-deprived CHL: chlorisondamine MEC: mecamylamine MLA: methyllcaconitine DHBE: dihyrdo-b-erythroidine Stone et al. Invest Ophthalmol Vis Sci (2001)

  26. Nitric oxide analogs - Inhibition via a retinal pathway? Chicks treated with 180 mM l-NAME & -16 D lens (significant effects observed at doses>60 mM) l-NAME inhibitsoscillatorypotentials Fujikado et al. Ophthalmic Res (2001)

  27. Retinally-active drugs “work” They tell us about mechanisms BUTHow safe is the retina as a site of action for myopia control?

  28. The neglected targets - IOP, scleral growth & ocular rhythms • Targeted drugs • timolol • latanoprost • melatonin

  29. IOP, timolol & myopia control in chicks -15 D lens Diffusers Schmid et al. Exp Eye Res (2001) IOP decrease 8-10%, FDM; 13-14% LIM

  30. Latanoprost & myopia inhibitionin chicks - Effect via IOP (or PGs)? Form-deprived for 1 week BID X2, separated by 3 days BID Jin & Stjernschantz Acta Ophthalmol Scand (2000)

  31. The sclera - An alternative site of action for myopia control drugs? Curtin, 1985

  32. b-xyloside study Inhibition PG synthesis in chicks Rada et al.Exp Eye Res (2002)

  33. The sclera - An alternative site of action for antimuscarinic drugs? • Evidence • ECMA lesions • cell culture

  34. ECMA lesions, atropine & myopia in chicks Chicks treated with 25 nmol ECMA, +/- form deprivation & 40 ug atropine daily for 6 days Fischer et al. Brain Res (1998)

  35. Scleral cell culture & myopia in chicks Thymidine incorporation Sulfate incorporation by chondrocytes Atr: atropine Pir: Pirenzepine DAMP: 4-DAMP Lind et al. Invest Ophthal Vis Sci (1998)

  36. So what about humans?

  37. Timolol - Not effective for human myopia control! 0.25% timolol, BID Jensen Acta Ophthalmologica (1991)

  38. Atropine & human myopiaRecent findings are promising! Refraction changes over 18 months - 0.25% atropine + multifocals cf. multifocal & single vision spectacles Shih et al.Acta Ophthalmol Scand (2001)

  39. Pirenzepine & human myopiaRumor has it that results from on-going trials are very promising!

  40. But is it just that simple?

  41. Myopia control treatment - There are significant unresolved issues • Required treatment is very long term • chronically applied topical drugs causeocular 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?

  42. Is oral administration a possibility?Pirenzepine works in chicks Flitcroft, Troilo & Wildsoet 8th International Myopia Meeting (2000)

  43. Other drug options - Retinoic acid & effects on eye growth Chick scleral punches assayed in culture Mertz & Wallman Exp Eye Res (2001)

  44. Fos-labelling Control 2hr treated Antisense drugs & eye growth control in chicks AODN: antisense oligodeoxynucleotide McGuire & Stell (2000)

  45. Drugs for myopia control The best way forward?

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