Pharmacological Aspects of Myopia

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Pharmacological Aspects of Myopia
Myopia Strategies for the 21st Century

• Christine Wildsoet
• University of California Berkeley

Christine Wildsoet, OD, PhD UC Berkeley
Optometry vision.berkeley.edu/VSP/CW
wildsoet_at_spectacle.berkeley.edu
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Pharmacological intervention - not a very new
idea

• Bedrossian atropine study (1966)
• Underlying assumption
• Excessive near work involved
• Excessive accommodation implicated

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Bedrossian (1966) Study

• 1 atropine nightly
• age 7-13 yr
• progressing myopes
• refractions only

Swap overtime
Incr. progression
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Pharmacological intervention - options for
treatment
Scleral target

• Determining factors
• Is myopia genetic /or nonvisual?
• Are visual factors involved?

Animal models
Retinal ( higher level) target
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Animal models
Lesson from Bedrossian Measure eye length
refractive errors
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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-b
• VIP
• Melatonin
• Enkephalins

Retina - target for many studies!
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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?
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The retina as a drug targetMany transmitters,
many drug options!
Amacrine cells their transmitters of
particular interest
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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
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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)
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DA analogs - The earliest study?Chicks form
deprivation myopia
Stone et al. Proc Nat Acad Sci (1989)
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Apomorphine chicks Effects on lens-induced
myopia
-15 D lenses worn from 8 days for 4
days
Schmid Wildsoet ARVO (1998)
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Apomorphine, FDM monkeys
Form deprived (FD) 5-8 monthswith opaque contact
lenses
Tigges et al. Invest Ophthalmol Vis Sci
(1991)
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Apomorphine, RPE scleral growth in chick
Retinal pigment epitheium cultured with scleral
chondrocytes /- apomorphine
Seko et al. Cell, Biochemistry Function
(1997)
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Dopaminergic effects - Some apparent
inconsistencies

• dopamine turnover decreases in FDM LIM
• BUT
• dopamine antagonists can also inhibit eye growth
• agonistsantagonists enhance myopia
• 6-OHDA inhibits FDM, not LIM
• reserpine inhibits both FDM LIM

FDM form deprivation myopia LIM lens induced
myopia
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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)
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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!
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Antimuscarinic drugs -the earliest chick study
Increasing dose
Lid suture for 2 weeks daily SC
injections Atropine (Atr, nonselective) Pirenzepi
ne (Pir M1) Methoctramine (Met M2) 4-DAMP
(DAMP, M3)
Stone et al. Exp Eye Res (1991)
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M4-selective antimuscarinic drugs also work!
Chicks were form deprived treated with
himbacine, a M4 selective agent
Cottriall et al. NeuroReport (2001)
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Atropine lens-induced myopia in chicks
Intravitreal injections 25 ug atropine every
other day measured after 7 days
Wildsoet, McBrien Clark ARVO (1994)
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Antimuscarinic drugs - They also work in mammals
primates
Monkey
Tigges et al. Optom Vis Sci (1999)
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DA analogs antimuscarinic drugs Can they be
combined to improve efficacy?
Chicks treated from day 8 - day 12
Schmid Wildsoet Proc Aust Neurosci Soc
(2000)
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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)
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Retinally-active drugs -Other possibilities

• Nicotinic analogs
• NOS inhibitors

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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)
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Nitric oxide analogs - Inhibition via a retinal
pathway?
Chicks treated with 180 mM l-NAME -16 D lens
(significant effects observed at
doses60 mM)
l-NAME inhibitsoscillatorypotentials
Fujikado et al. Ophthalmic Res (2001)
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Retinally-active drugs work They tell us about
mechanisms BUTHow safe is the retina as a site
of action for myopia control?
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The neglected targets - IOP, scleral growth
ocular rhythms

• Targeted drugs
• timolol
• latanoprost
• melatonin

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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
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Latanoprost myopia inhibition in chicks -
Effect via IOP (or PGs)?
Form-deprived for 1 week
BID
X2, separated by 3 days
BID
Jin Stjernschantz Acta Ophthalmol Scand
(2000)
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The sclera - An alternative site of action for
myopia control drugs?
Curtin, 1985
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??b-xyloside study Inhibition PG synthesis in
chicks
Rada et al. Exp Eye Res (2002)
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The sclera - An alternative site of action for
antimuscarinic drugs?

• Evidence
• ECMA lesions
• cell culture

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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)
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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)
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So what about humans?
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Timolol - Not effective for human myopia control!
0.25 timolol, BID
Jensen Acta Ophthalmologica (1991)
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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)
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Pirenzepine human myopiaRumor has it that
results from on-going trials are very promising!
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But is it just that simple?
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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?

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Is oral administration a possibility?Pirenzepine
works in chicks
Flitcroft, Troilo Wildsoet 8th International
Myopia Meeting (2000)
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Other drug options - Retinoic acid effects on
eye growth
Chick scleral punches assayed in culture
Mertz Wallman Exp Eye Res (2001)
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Antisense drugs eye growth control in chicks
AODN antisense oligodeoxynucleotide
McGuire Stell (2000)
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Drugs for myopia control
The best way forward?