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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
Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu
Pharmacological intervention
- not a very new idea
Bedrossian atropine study (1966)Underlying assumption
Excessive near work involvedExcessive accommodation
implicated
Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu
Bedrossian (1966) Study1% atropine nightlyage 7-13 yr progressing myopesrefractions only
Swap overtime
Incr. progression
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
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
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 studiedbFGFTNF-VIPMelatoninEnkephalins
Retina - target for many studies!
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?
Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu
The retina as a drug targetMany transmitters, many drug
options!
Amacrine cells & their transmitters of particular interest
Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu
DA analogs - First to be tested with animal modelsRationale
DA regulates retinal coupling
DA influences retinal spatial processing
Low retinal DA
High retinal DA
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 developmentchickmonkey Key work in this area
Stone, Laties & Tigges (chicks & monkeys)Schaeffel lab (chicks)Stell lab (chicks)Wildsoet & Schmid (chicks)Seko (chicks)
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)
Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu
Apomorphine & chicks Effects on lens-induced myopia
Schmid & WildsoetARVO (1998)
-15 D lenses: worn from 8 days for 4 days
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 monthswith opaque contact lenses
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
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 & LIMBUT 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 myopiaLIM: lens induced myopia
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 developmentchicks tree shrewsmonkeyshumans
Key work in this areaStone, Laties & Tigges (chicks/monkeys)Schaeffel lab (chicks)McBrien lab (chicks & tree shrews)Wildsoet & Schmid (chicks)Wallman lab (chicks)Shih (chicks)SERI (chicks)
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 musclesare nicotinic!
Ciliary muscle is not the site of actionAccommodation not the target!
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; M1)Methoctramine (Met; M2)4-DAMP (DAMP, M3)
Increasing dose
Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu
M4-selective antimuscarinic drugs also work!
Cottriall et al. NeuroReport (2001)
Chicks were form deprived & treated with himbacine, a M4 selective agent
Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu
Atropine & lens-induced myopia in chicks
Wildsoet, McBrien & ClarkARVO (1994)
Intravitreal injections25 ug atropine every other day;measured after 7 days
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
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
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
Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu
Retinally-active drugs -Other possibilities
Nicotinic analogsNOS inhibitors
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: chlorisondamineMEC: mecamylamineMLA: methyllcaconitineDHBE: dihyrdo--erythroidine
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 inhibitsoscillatorypotentials
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?
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
Scleral structure(collagen, extracellular matrix) IOP
Scleralcompliance
Eye growth
Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu
IOP, timolol & myopia control in chicks
-15 D lens Diffusers
IOP decrease 8-10%, FDM; 13-14% LIMSchmid et al. Exp Eye Res (2001)
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
BID
X2, separated by 3 days
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
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)
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?
EvidenceECMA lesionscell culture
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
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: atropinePir: PirenzepineDAMP: 4-DAMP
Thymidine incorporation
Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu
So what about humans?
Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu
Timolol - Not effective for human myopia
control!
JensenActa Ophthalmologica (1991)
0.25% timolol, BID
Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu
Atropine & human myopiaRecent findings are promising!
Shih et al.Acta Ophthalmol Scand (2001)
Refraction changes over 18 months - 0.25% atropine + multifocals cf. multifocal & single vision spectacles
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!
Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu
But is it just that simple?
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
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)
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
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)
Control 2hr treated
Fos-labelling
AODN: antisense oligodeoxynucleotide
Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu
Drugs for myopia control
The best way forward?
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