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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 • [email protected] .

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Pharmacological Aspects of Myopia

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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 • [email protected]


Pharmacological intervention - not a very new idea

Bedrossian atropine study (1966)

  • Underlying assumption

    • Excessive near work involved

    • Excessive accommodation implicated


Bedrossian (1966) Study

  • 1% atropine nightly

  • age 7-13 yr

  • progressing myopes

  • refractions only

Swap overtime

Incr. progression


Pharmacological intervention - options for treatment

  • Determining factors

    • Is myopia genetic &/or nonvisual?

    • Are visual factors involved?

Scleral target

Animal models

Retinal (& higher level)target


Animal models

Lesson from Bedrossian:

Measure eye length + refractive errors


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!


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?


The retina as a drug targetMany transmitters, many drug options!

Amacrine cells & their transmitters of particular interest


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


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)


DA analogs - The earliest study?Chicks & form deprivation myopia

Stone et al.

Proc Nat Acad Sci (1989)


Apomorphine & chicks Effects on lens-induced myopia

-15 D lenses: worn from 8 days for 4 days

Schmid & Wildsoet

ARVO (1998)


Apomorphine, FDM & monkeys

Form deprived (FD) 5-8 monthswith opaque contact lenses

Tigges et al.

Invest Ophthalmol Vis Sci (1991)


Apomorphine, RPE & scleral growth in chick

Retinal pigment epitheium cultured with scleral chondrocytes +/- apomorphine

Seko et al.

Cell, Biochemistry & Function (1997)


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


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)


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!


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)


M4-selective antimuscarinic drugs also work!

Chicks were form deprived & treated with himbacine, a M4 selective agent

Cottriall et al.

NeuroReport (2001)


Atropine & lens-induced myopia in chicks

Intravitreal injections

25 ug atropine every other day;

measured after 7 days

Wildsoet, McBrien & Clark

ARVO (1994)


Antimuscarinic drugs - They also work in mammals & primates

Monkey

Tigges et al.

Optom Vis Sci (1999)


DA analogs + antimuscarinic drugsCan they be combined to improve efficacy?

Chicks: treated from day 8 - day 12

Schmid & WildsoetProc Aust Neurosci Soc (2000)


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)


Retinally-active drugs -Other possibilities

  • Nicotinic analogs

  • NOS inhibitors


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)


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)


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


The neglected targets - IOP, scleral growth & ocular rhythms

  • Targeted drugs

  • timolol

  • latanoprost

  • melatonin


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


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)


The sclera - An alternative site of action for myopia control drugs?

Curtin, 1985


b-xyloside study Inhibition PG synthesis in chicks

Rada et al.Exp Eye Res (2002)


The sclera - An alternative site of action for antimuscarinic drugs?

  • Evidence

    • ECMA lesions

    • cell culture


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)


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)


So what about humans?


Timolol - Not effective for human myopia control!

0.25% timolol, BID

Jensen

Acta Ophthalmologica (1991)


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)


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


But is it just that simple?


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?


Is oral administration a possibility?Pirenzepine works in chicks

Flitcroft, Troilo & Wildsoet 8th International Myopia Meeting (2000)


Other drug options - Retinoic acid & effects on eye growth

Chick scleral punches assayed in culture

Mertz & Wallman

Exp Eye Res (2001)


Fos-labelling

Control

2hr treated

Antisense drugs & eye growth control in chicks

AODN: antisense oligodeoxynucleotide

McGuire & Stell (2000)


Drugs for myopia control

The best way forward?


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