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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

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
Pharmacological intervention - not a very new idea

Bedrossian atropine study (1966)

  • Underlying assumption
    • Excessive near work involved
    • Excessive accommodation implicated
bedrossian 1966 study
Bedrossian (1966) Study
  • 1% atropine nightly
  • age 7-13 yr
  • progressing myopes
  • refractions only

Swap overtime

Incr. progression

pharmacological intervention options for treatment
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
Animal models

Lesson from Bedrossian:

Measure eye length + refractive errors

drug options results from experimental studies clinical trials
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
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 target many transmitters many drug options
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
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 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
DA analogs - The earliest study?Chicks & form deprivation myopia

Stone et al.

Proc Nat Acad Sci (1989)

apomorphine chicks effects on lens induced myopia
Apomorphine & chicks Effects on lens-induced myopia

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

Schmid & Wildsoet

ARVO (1998)

apomorphine fdm monkeys
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
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
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 - 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
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
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)

m 4 selective antimuscarinic drugs also work
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
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
Antimuscarinic drugs - They also work in mammals & primates

Monkey

Tigges et al.

Optom Vis Sci (1999)

da analogs antimuscarinic drugs can they be combined to improve efficacy
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
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
Retinally-active drugs -Other possibilities
  • Nicotinic analogs
  • NOS inhibitors
nicotinic analogs myopia in chicks
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
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)

slide27
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
The neglected targets - IOP, scleral growth & ocular rhythms
  • Targeted drugs
  • timolol
  • latanoprost
  • melatonin
iop timolol myopia control in chicks
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 inhibition in chicks effect via iop or pgs
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 antimuscarinic drugs
The sclera - An alternative site of action for antimuscarinic drugs?
  • Evidence
    • ECMA lesions
    • cell culture
ecma lesions atropine myopia in chicks
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
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)

timolol not effective for human myopia control
Timolol - Not effective for human myopia control!

0.25% timolol, BID

Jensen

Acta Ophthalmologica (1991)

atropine human myopia recent findings are promising
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)

myopia control treatment there are significant unresolved issues
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
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
Other drug options - Retinoic acid & effects on eye growth

Chick scleral punches assayed in culture

Mertz & Wallman

Exp Eye Res (2001)

antisense drugs eye growth control in chicks

Fos-labelling

Control

2hr treated

Antisense drugs & eye growth control in chicks

AODN: antisense oligodeoxynucleotide

McGuire & Stell (2000)

drugs for myopia control
Drugs for myopia control

The best way forward?

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