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HANDBOOKOFBASICANDCLINICAL OCULARPHARMACOLOGYAND THERAPEUTICS
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HANDBOOKOF BASICAND CLINICALOCULAR PHARMACOLOGY AND
THERAPEUTICS
Editedby
SUNNY E.OHIA
OphthalmicPharmacologyResearchLaboratory,DepartmentofPharmaceuticalSciences, JoanM.LafleurCollegeofPharmacyandHealthSciences,TexasSouthernUniversity,Houston,TX,UnitedStates
NAJAM A.SHARIF
GlobalAlliancesandExternalResearch,OphthalmologyInnovationCenter,SantenInc.,Emeryville,CA,UnitedStates DepartmentofPharmacySciences,CreightonUniversity,Omaha,NE,UnitedStates SingaporeEyeResearchInstitute(SERI),Singapore,Singapore Duke-NationalUniversityofSingaporeMedicalSchool,Singapore DepartmentofSurgery&Cancer,ImperialCollegeofScienceandTechnology, St.Mary’sCampus,London,UnitedKingdom DepartmentofPharmaceuticalSciences,CollegeofPharmacyandHealthSciences, TexasSouthernUniversity,Houston,TX,UnitedStates DepartmentofPharmacologyandNeuroscience,UniversityofNorthTexasHealthSciencesCenter, FortWorth,TX,UnitedStates InstituteofOphthalmology,UniversityCollegeLondon,London,UnitedKingdom
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Notices
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Practitionersandresearchersmustalwaysrelyontheirownexperienceandknowledgeinevaluatingandusingany information,methods,compounds,orexperimentsdescribedherein.Inusingsuchinformationormethodstheyshouldbe mindfuloftheirownsafetyandthesafetyofothers,includingpartiesforwhomtheyhaveaprofessionalresponsibility.
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Dedication
Dedicatedtomywife,Dr.EkanemOhia,mychildren,andmystudents, past,present,andfuture
SunnyE.Ohia
Dedicatedtomyparents,wife,children,andmymanymentors,supporters,and collaboratorsatmanyglobaluniversitiesandpharmacompanies.Ifeelblessedto havebeenasmallcontributortowardsneuroscienceandophthalmologyresearch anddrugdiscovery NajamA.Sharif
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Listofcontributorsxvii
Prefacexxi
Acknowledgmentsxxiii
1.Theeyeasatargetfordrugsandother treatmentmodalities1
Subchapter1.1Anatomyand pathology1
MartinaC.Herwig-Carl,KarinU.Loeffler
Introduction1
Anatomyandoverviewofeyediseases2
Anatomy2
Briefoverviewofeyediseaseswith clinico-pathologiccorrelation7
References14
Subchapter1.2Ocularbiochemistry17
MarshalynG.McKoy
Aqueoushumor17
Productionofaqueoushumor17
Compositionofaqueoushumor18
Vitreoushumor20
Retina21
Structureandfunctionofneuralpathwayofthe retina21
Phototransduction22
Oxidativestressintheretina23
References23
Subchapter1.3Physiology27
AnthoniaOkolie,FatimaMuili,YaFatouNjie-Mbyeand SunnyE.Ohia
Anteriorsegmentoftheeye27
Posteriorsegmentoftheeye29
References31
Subchapter1.4Receptors,ionchannels, andsignaltransductionpathwaysas targetsfordruginterventionto mitigateoculardiseases33
NajamA.Sharif
Introduction33
Phospholipase-C-coupledreceptors,januskinase pathway,transcription,andimmunogenicfactors inmediatingconjunctivitis41
Roleofmultipleofreceptor-signalingpathways involvedincausingandtreatingglaucoma44
Receptor-tyrosine-kinasesignalingpathwayscausing age-relatedmaculardegeneration47
Concludingremarks49
References49
2.Ocularautonomicphysiologyand pharmacology55
MarshalynMcKoy,YaFatouNjie-MbyeandCatherineA.Opere
Introduction55
Structureoftheocularautonomicnervous system55
Functionoftheocularautonomicnervous system57
Autonomiccontrolofpupildiameter58
Mechanismsofautonomiccontractionsofpupillary muscles58
Mydriaticandmioticagents59
Autonomicregulationofocular accommodation60
Autonomicregulationofocularbloodflow61
Autonomicregulationofintraocularpressure62
Summary63
References64
3.Oculardrugdiscoveryand development67
Subchapter3.1Drugdiscoveryin ophthalmology:creatingnewchemical entitiesinnewclassesofdrugs
MitchellA.deLongandJillSturdivant
Introduction/overview67
Type3Bophthalmicdrugdiscovery— prostaglandinanalogsandROCK inhibitors69
Modernophthalmicdrugdiscovery—rhokinase inhibitors74
RelatedinvestigationsofROCKinhibitors84
Othercompanies’ROCKinhibitorefforts84
Conclusion85
References86
Furtherreading88
Subchapter3.2Screeningstrategiesfor drugdiscovery-focusonocular hypertension91
NajamA.Sharif
Introduction91
Invitroassaysforscreeningpotentialocular hypotensivecompounds106
Exvivoocularmodelsfordrug characterization107
AnimalmodelsofOHTdiseaseandinvivo studies108
Conclusions110
References111
Furtherreading116
Subchapter3.3Therapeuticmodalityaspects insafetyandefficacyofoculardrugs119
AishwaryaKundu,ChiungkuangChenandSreenivasuMudumba
Pharmacokineticsofoculardrugs120
Bioavailabilityoftopicaldrugs121
Bioavailabilityofperioculardrugs121
Bioavailabilityofintraoculardrugs122
Drugresidenceandsustaineddelivery122
Pharmacodynamicsofoculardrugs124
Safetyofoculardrugs126
Aggregation126
Impurities126
Antidrugantibodies127
Overview128
Conclusion128
References129
Subchapter3.4Investigational newdrug-enablingstudiesforocularand othertherapeutics131
NajamA.Sharif
Introduction131
Investigationalnewdrugstudyapplications135
Studiesanddatatopermitinvestigationalnewdrug applicationfiling136
Pharmaceuticalagentquality138
Primarypharmacologyoftheactiveproduct ingredient138
Secondarypharmacology/safety pharmacology138
Pharmacokineticstudies142
Toxicologicalevaluationstudies142
Genotoxicitystudies144
Conclusions145
References145
Subchapter3.5Preclinicalocular regulatoryscience—investigational newdrug-enablingstudies147
FranzBuchholzer
References149
Subchapter3.6Ocularclinicalregulatory sciences151
FranzBuchholzer
References153
4.Drugformulation,delivery,andocular pharmacokinetics155
Subchapter4.1Ocularformulationand noveldrugdeliverysystems
VivekAgrahariandOnkarN.Singh
Introduction155
Routesofoculardrugadministrationandassociated barriers157
Keyconsiderationsinthedevelopmentof ophthalmicformulations160
Physicalpropertiesofthedrugs160
Roleofexcipients161
Sterility162
Ophthalmicformulations163
Conventionaloculardosageforms163
Novelcontrolledreleaseophthalmic formulations167
References175
Subchapter4.2Ocular pharmacokinetics179
JamesE.Chastain
Introduction179
Anatomy/physiology179
Topicalocularadministration181
Transcornealabsorption183
Absorptionkinetics185
Conjunctival/scleralabsorption189
Topicaloculardistribution191
Eliminationfollowingtopicalocular administration195
Ocularpharmacokineticmodels—frontofthe eyedelivery197
Intravitrealadministration199
Intravitrealdrugdistributionandelimination200
Vitrealpharmacokineticmodels202
Otherroutesofadministration205
Systemicadministration207
Ocularmetabolism207
Hydrolyticenzymes208
CytochromeP450enzymes208
PhaseIImetabolism209
Othermetabolizingenzymes210
Transporters210
Conclusion211
References212
5.Pharmaco-devicestherapyfor glaucoma221
Subchapter5.1Theimportanceofdistal outflowresistanceintheregulationof intraocularpressure221
FionaS.McDonnell,MeganS.Kuhn,AlexA.Huang,
W.DanielStamer
Introduction221
Intraocularpressureregulation222
Aqueoushumoroutflow222
Proximal distaloutflow communication224
Distaloutflowregulation226
Anatomy226
IOPhomeostasis230
Clinicalrelevanceofthedistalportionofthe outflowpathway235
Structuralandfunctionaloutflow imaging236
Outflowimagingandglaucoma therapeutics239
Summaryandfuturedirections240
References241
Subchapter5.2Variousformsof glaucomaandtheirtreatments251
NajamA.Sharif
Introduction251
Primaryopen-angleglaucomaandits treatment252
Normotensiveglaucomaanditstreatment253
Primaryclosed-angleglaucomaandits treatment254
Pharmaceuticaltreatmentoptionsfor glaucomas254
Lasertreatmentstoreduceintraocular pressure262
Surgicalprocedurestolowerintraocular pressure262
Minimallyinvasiveglaucomasurgeries-baseddevices forloweringintraocularpressure263
Neuroprotectionforglaucomatreatment264
Conclusions266
References267
Furtherreading271
Subchapter5.3Glaucoma pharmacology289
AllisonStradiottoandSadeKosoko-Lasaki
Definition289
Typesandpathophysiology289
Epidemiology290
Presentation290
Diagnosis291
Treatment291
Contents
Pharmacokinetics292
Prostaglandins292
Beta-adrenergicblockers293
Carbonicanhydraseinhibitors293
Sympathomimetics294
Parasympathomimetics294
Rho-associatedproteinkinaseinhibitor295
Hyperosmoticagents295
Combinationmedications295
Preservativeagents296
Lasersandsurgeries296
References296
Subchapter5.4Minimallyinvasive glaucomasurgicaldevices299
LeonardPinchukandOmarSadruddin
Acknowledgments305
References305
Subchapter5.5Genetherapyforocular hypertensionandglaucoma treatment309
NajamA.Sharif
Introduction309
Applicationofgenetherapytolowerintraocular pressure310
Genetherapyforneuroprotectionin glaucoma312
Conclusions313
References313
Subchapter5.6Retina brainaxisand neuroprotection317
YuMengLi,AndyK.Cheng,HaiderManzar,TimothyE.Yapand M.FrancescaCordeiro
Retina brainaxis317
Neuroprotection318
Memantine319
Brimonidine319
Citicoline319
CoenzymeQ10320
Ginkgobiloba320
Neurotrophins321
Futuredirections321
References322
6.Pharmacotherapyofretinal diseases325
Subchapter6.1Pharmacotherapyof retinaldiseases
YaFatouNjie-Mbye,KaluK.NgeleandOhia,S.E.
Basicscience325
Overviewoftheretina325
Therapeuticstrategiesfortreatmentofretinal diseases327
Intravitrealroute327
Periocularroutes327
Implants328
Otherroutes328
Pharmacologyofagentsusedinthetherapyof retinaldiseases328
Vascularendothelialgrowthfactors inhibitors329
Corticosteroids329
Ganciclovir330
Verteporfin330
Voretigene330
References331
Subchapter6.2Age-relatedmacular degenerationanditstreatment options333
AbuAbraham,KeiichiShibagakiandMasanaoToshimori
Epidemiology333
Clinicalcharacteristics333
Diagnosis334
Etiologyandpathogenesisofage-relatedmacular degeneration334
Treatments336
Bevacizumab337
Ranibizumab338
Aflibercept338
Brolucizumab338
Faricimab339
Concludingremarks339
References340
Subchapter6.3Pharmacotherapyof diabeticretinopathy343
PhilLuthert
Introduction343
Systemictherapy345
Controlofbloodglucose345
Controlofdyslipidemia346
Controlofhypertension346
Controlofsystemicinflammation/oxidative stress347
Localtherapy347
Antiangiogenesistherapy347
Efficacyofintravitrealantivascular endothelialcellgrowthfactortherapyfor proliferativediabeticretinopathywith andwithoutpanretinal photocoagulation348
Efficacyofintravitrealantivascularendothelial cellgrowthfactortherapyfordiabetic macularedema349
Complicationsofintravitrealvascular endothelialcellgrowthfactor349
Antiinflammatorystrategies350
Neuroprotectionfordiabeticmacular edema350
Pharmacotherapyasanadjunctto surgery350
Combinationpharmacotherapy351
Clinicalpathways351
Futuredirections351
References352
Subchapter6.4Inheritedretinal dystrophies357
BenjaminR.Yerxa
Inheritedretinaldystrophies357
Retinitispigmentosa357
Lebercongenitalamaurosis361
Ushersyndrome362
X-linkedretinoschisis363
Achromatopsia363
Choroideremia363
Stargardt364
Optogenetics365 References365
7.Pharmacotherapyofinflammatoryeye diseases367
Subchapter7.1Pharmacotherapyof inflammatoryeyediseases
DariushYalzadeh,CatherineA.Opere
Introduction367
Blepharitis368
Anatomicalstructuresinvolvedin blepharitis368
Drugs370
Pharmacokinetics370
Pharmacodynamics371
SideeffectsandInteractions373
Keratitis373
Anatomicalstructuresinvolvedin keratitis374
Drugs375
Pharmacodynamics378
Pharmacokinetics378
Sideeffectsandinteractions379
Uveitis379
Anatomicalstructuresinvolvedin uveitis380
Drugs382
Pharmacokinetics383
Pharmacodynamics384
Sideeffectsandinteractions385
References386
Subchapter7.2Noninfectiousanterior, posterior,andpanuveitisandtheir treatments389
AbuAbraham
Epidemiology389
Etiologyandpathogenesis389
Clinicalcharacteristicsanddiagnosis392
Anterioruveitis392
Posteriorsegmentuveitis(intermediate, posterior,andpanuveits)393
Treatments395
Topicalcorticosteroids395
Cycloplegics396
Nonsteroidalanti-inflammatorydrugs396
Periocularcorticosteroids397
Intravitrealcorticosteroids397
Systemiccorticosteroids398
Systemicimmunosuppressiveagents398
Biologicagents401
Concludingremarks401
References401
8.Etiologyandpharmacotherapyofocular surfaceallergicdiseases403
NajamA.Sharif
Introductionandoverview403
Epidemiologyandetiologyofhuman conjunctivitis404
Shorthistoryofdrugdiscoveryforseasonalallergic conjunctivitisandperennialallergic conjunctivitis406
Screeningstrategiesforocularantiallergic compounds407
Pharmacotherapeuticsforseasonalallergic conjunctivitisandperennialallergic conjunctivitistreatment408
Currentpharmacotherapyforseasonalallergic conjunctivitisandperennialallergic conjunctivitis415
Othertypesofallergicconjunctivitisandtheir treatments416
Conclusion418
References418
9.Pharmacotherapyofdryeyediseaseand ocularpain423
HidekiMiyake,PhilippeDaullandMouradAmrane
Dryeyediseaseandocularpain,their manifestationsandimpactonthedailylifeof patients423
Animalandcell-basedmodelsfordryeye disease424
Sjogrensyndromemodel425
Desiccationstressmodel426
Meibomianglanddysfunctionmodel427
Miscellaneousmodel428
Clinicalaspectsofdryeyedisease429
Anti-inflammatorytreatments429
Ocularpain(dryeyesymptomsandinjuries)436
Conclusion439
References440
10.Pharmacotherapiesformyopiaand ocularrefractiveerrors447
Subchapter10.1Thepharmocotherapyof myopia—animalstudiesandclinicaltrials
LiLianFoo,WeiYanNg,AudreyChia
Introduction447
Animalstudiesofpharmacologicalagents448
Muscarinicacetylcholinereceptorsand antagonists448
TranscriptionfactorZENK450
Dopamine450
Nitricoxide451
Adenosinereceptor452
Gamma-aminobutyricacid452
Clinicalstudiesofpharmacologicalagents453
Muscarinicreceptorantagonists453
Beta-adrenergicreceptorantagonists458
Adenosinereceptorantagonist459
Summary459
References460
Subchapter10.2Cataractsand presbyopia465
PoojaGudibandaandLeahMakley
Lensstructureandfunctions465
Presbyopiaandcataract:age-relateddegenerationof lensfunction468
Presbyopia469
Cataract470
Dysfunctionallenssyndrome:anintermediatestage oflensaging471
Acloserlookattheaginglens471
Pharmacologicaltreatmentapproaches472
Crystallinconformationcorrectorsinpresbyopia andcataract472
Mioticsfortransientcorrectionof presbyopia473
Preclinicalmodelsofpresbyopiaandcataracts474
Hereditarycataractmodels474
Wildtypemodelanimalswithnaturally occurringcataracts475
Inducedmodelsofcataract476
Animalmodelsofpresbyopia476
Imagingmodalities,assessments,andendpointsfor presbyopiaandcataracts477
SummaryandOutlook478
References478
11.Pharmacotherapyofocularinfectious diseases483
NajamA.Sharif
Introduction483
Bacterialandviralinfectionsandtheir treatments483
Ocularfungaldiseasesandtreatments485 Conclusion488 References488
12.Ocularsideeffectsofdrugs administeredsystemicallyfortreatmentof nonoculardiseases491
DariushYalzadeh,AnthoniaOkolie,FatimaMuili, YaFatouNjie-Mbye,CatherineA.Opere,OdochiOhia-Nwoko andSunnyE.Ohia
Introduction491
Drugsactingonthecardiovascularsystem492
Drugsactingonthecentralnervoussystem493
Antiinflammatorydrugs495
Nonsteroidalantiinflammatorydrugs495
Corticosteroids495
Antiviralandantimicrobialdrugs496
AntiviralDrugs496
Antimicrobialdrugs496
Anticancerdrugs499
Drugsusedforskindiseases499
Summary499 References503
13.Currentandemergingtechniques/ technologiesinocularresearchanddrug/ devicedevelopment509
Subchapter13.1Genome-wideassociation studiestounravelgeneticsofocular diseases
NajamA.Sharif
Introduction509
SpecificexamplesofGWASfordifferentformsof glaucoma511
GWASformyopia513
Conclusions524
References525
Furtherreading527
Subchapter13.2Single-cellgenetics approachinophthalmology529
AlexLeung,YouichiShinozaki,SchuichiKoizumiand Shin-ichiOhnuma
Cellsintheeye529
Cellcharacterizationbysingle-cellmRNA expressionprofiling530
Next-generationsequencing531
Single-cellisolationtechnology531
Bioinformaticalanalysismethods532
Retinalcellsubtypeidentification533
Cellnumbersandreadnumbers535
Single-cellanalysisofretinaldiseases535
FuturedevelopmentofmRNAexpressionprofiling technology537
References538
Subchapter13.3Mullerglia-derived exosomesandtheirmicroRNA cargo potentialforglaucoma therapies543
WilliamD.B.LambandG.AstridLimb
Introduction543
Neurotrophinsandtheirprotectiverolesin maintainingretinalganglioncell survival544
Contributionofoxidativestressto glaucomatousdamage—considerationsfor antioxidanttherapies545
Experimentalandclinicalapproachesfor glaucomaneuroprotectionbasedonthe applicationofneurotrophicfactors546
Stemcelltransplantationasaneuroprotective approachtotreatglaucoma547
Extracellularvesicles548
Potentialofextracellularvesiclesderivedfrom Mu¨llergliaforthedevelopmentof neuroprotectivestrategiesinglaucoma550
Micro-RNAsandtheirpotentialforneuroprotective glaucomatherapies551
Conclusionsandfuturetrends553
References554
Subchapter13.4Geneticsandother techniquestocreatenovelanimalmodels forocularresearch561
NajamA.Sharif
Introduction561
Cornealandconjunctivaldiseases—animal models562
Ocularhypertension/glaucomaandanimal models562
Cataractsandanimalmodels565
Age-relatedmaculardegenerationandanimal models566
Diabeticretinopathyandanimalmodels567
Conclusions568
References568
Furtherreading574
Subchapter13.5Imagingofapoptosing retinalcellsforearlydiagnosis577
DaliaAbdulhussein,TimothyE.YapandM.FrancescaCordeiro
Rationaletodetectionofapoptosingretinalcell technology577
Thedetectionofapoptosingretinalcell technique577
Applications578 References579
Subchapter13.6Optogeneticapproaches togenetherapyforvisionrestorationin retinaldegenerativediseases581
SamarendraMohanty,ChinenyeIdigo,AnantaAyyagariand DarrylNarcisse
Introduction581
Theretina581
Inheritedretinaldegenerations582
Maculardegeneration582
Visionrestorationtechnologies583
Optogenetics584 Opsins585
Mechanismofphototransduction585
Applicationsofoptogeneticsforvision restoration586
Mammalianversusmicrobialopsins586
Kinetics587
Preclinicalstudiesofnativeandengineered opsins587
Deactivationandrecovery591
Genedeliverymethods592
Viraldelivery592
Lasergenedelivery595
Electroporation595
Nonopsinoptogeneticstrategies596
Optogeneticretinalprostheses596
Upconversionnanoparticles597
Chemicalphotoactivableswitches597
Optogeneticclinicaltrials598
Concludingremarksandfuturedirections599
Engineeringcomplexityintorestoredretinal circuitry600
Developingbetterretinadegeneration model600
Nonviraldeliveryofopsin-genestotargeted retinalcellsandregions(s)ofinterest600
References601
Subchapter13.7Multispecificbiologicsin opthalmology607
ChiungkuangChen,AishwaryaKunduandSreenivasuMudumba
Strategiesindevelopingbispecificormultispecific biologics607
Designanddevelopmentofbispecificbiologics609
Developmentthroughpreclinicalandclinical phases612
Conclusion613
References613
Subchapter13.8CRISPR Cas9:current andfutureutilitiesinoculardiseases615
SamYacoub,AkashRaolaandGulabZode
Introductiontogenomeediting615
Toolsforgenomeediting:ZFNs,TALENs,and CRISPR615
OverviewoftheCRISPR/Cas9system616
TypesofCRISPR Casenzymes617
DNArepair:nonhomologousend-joiningversus homology-directedrepair618
CRISPR Cas9:currentutilityinocular research618
Glaucoma619
Ocularangiogenesis619
Lebercongenitalamaurosis620
CRISPR Cas9:clinicaltrials621
Conclusions621
References621
Subchapter13.9DNAmethylation: itsroleinretinalhealthanddiseases625
ShahidHusain
DNAmethylation625
DNAmethylationwriters627
DNAmethylationerasers627
DNAmethylationreaders628
RolesofDNAmethylationinretina development628
DNAmethylationandeyediseases629 DNAmethylationanduveitis629
DNAmethylationandage-relatedmacular degeneration630 DNAmethylationanddiabeticretinopathy630 DNAmethylationandglaucoma631
Conclusions632
Acknowledgment632
References632
Index637
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Listofcontributors
DaliaAbdulhussein TheImperialCollege OphthalmicResearchGroup(ICORG), ImperialCollegeLondonNW,London, UnitedKingdom
AbuAbraham OphthalmologyInnovation Center,SantenInc.,Emeryville,CA,United States;VitreousandRetinaTherapeuticArea, OphthalmologyInnovationCenter,Santen Inc.,Emeryville,CA,UnitedStates
VivekAgrahari CONRAD,EasternVirginia MedicalSchool(EVMS),Norfolk,VA,United States
MouradAmrane OphthalmicInnovation Center,SantenPharmaceuticals,Evry,France
AnantaAyyagari NanoscopeTechnologies LLC,Arlington,TX,UnitedStates; NanoscopeTherapeuticsInc,Bedford,TX, UnitedStates
FranzBuchholzer GlobalRegulatoryAffairs, SantenSwitzerlandSA,Geneva,Switzerland
JamesE.Chastain NovartisInstitutesfor BioMedicalResearch,Cambridge,MA, UnitedStates
ChiungkuangChen TherapeuticModality Innovation,OphthalmologyInnovation Center,SantenInc.,Emeryville,CA,United States
AndyK.Cheng TheImperialCollege OphthalmicResearchGroup(ICORG), ImperialCollegeLondonNW,London, UnitedKingdom
AudreyChia SingaporeEyeResearchInstitute, Singapore,Singapore
M.FrancescaCordeiro TheImperialCollege OphthalmicResearchGroup(ICORG), ImperialCollegeLondonNW,London, UnitedKingdom;GlaucomaandRetinal NeurodegenerationGroup,UCLInstituteof
Ophthalmology,London,UnitedKingdom; TheWesternEyeHospital,ImperialCollege HealthcareNHSTrust(ICHNT),London NW,UnitedKingdom
PhilippeDaull OphthalmicInnovationCenter, SantenPharmaceuticals,Evry,France
MitchellA.deLong AeriePharmaceuticals, Durham,NC,UnitedStates;Departmentof Chemistry,DukeUniversity,Durham,NC, UnitedStates
LiLianFoo SingaporeEyeResearchInstitute, Singapore,Singapore
PoojaGudibanda ViewPointTherapeutics, Inc.,SanFrancisco,CA,UnitedStates
MartinaC.Herwig-Carl Departmentof Ophthalmology,DivisionofOphthalmic Pathology,UniversityHospitalBonn,Bonn, Germany
AlexA.Huang DepartmentofOphthalmology, UCSD,SanDiego,CA,UnitedStates
ShahidHusain Departmentof Ophthalmology,MedicalUniversityofSouth Carolina,Charleston,SC,UnitedStates
ChinenyeIdigo NanoscopeTechnologiesLLC, Arlington,TX,UnitedStates
SchuichiKoizumi Departmentof Neuropharmacology,InterdisciplinaryGraduate SchoolofMedicine,UniversityofYamanashi, Chuo,Japan;GLIACenter,Interdisciplinary GraduateSchoolofMedicine,Universityof Yamanashi,Chuo,Japan
SadeKosoko-Lasaki DepartmentofSurgery (Ophthalmology),SchoolofMedicine, CreightonUniversity,Omaha,NE,United States
MeganS.Kuhn Departmentof Ophthalmology,DukeUniversity,Durham, NC,UnitedStates
AishwaryaKundu TherapeuticModality Innovation,OphthalmologyInnovation Center,SantenInc.,Emeryville,CA,United States
WilliamD.B.Lamb UCLInstituteof OphthalmologyandNIHRBiomedical ResearchCentreatMoorfieldsEyeHospital, London,UnitedKingdom
AlexLeung UCLInstituteofOphthalmology, UniversityCollegeLondon,London,United Kingdom
YuMengLi TheImperialCollegeOphthalmic ResearchGroup(ICORG),ImperialCollege LondonNW,London,UnitedKingdom
G.AstridLimb UCLInstituteof OphthalmologyandNIHRBiomedical ResearchCentreatMoorfieldsEyeHospital, London,UnitedKingdom
KarinU.Loeffler Departmentof Ophthalmology,DivisionofOphthalmic Pathology,UniversityHospitalBonn,Bonn, Germany
PhilLuthert InstituteofOphthalmology UniversityCollegeLondon,London,United Kingdom
LeahMakley ViewPointTherapeutics,Inc., SanFrancisco,CA,UnitedStates
HaiderManzar TheImperialCollege OphthalmicResearchGroup(ICORG), ImperialCollegeLondonNW,London, UnitedKingdom
FionaS.McDonnell Departmentof Ophthalmology,DukeUniversity,Durham, NC,UnitedStates
MarshalynG.McKoy DepartmentofBasic MedicalSciences,TheUniversityoftheWest Indies,Mona,Kingston,Jamaica
HidekiMiyake OphthalmicInnovation Center,SantenPharmaceuticals,Nara,Japan
SamarendraMohanty Nanoscope TechnologiesLLC,Arlington,TX,United States;NanoscopeTherapeuticsInc,Bedford, TX,UnitedStates
SreenivasuMudumba TherapeuticModality Innovation,OphthalmologyInnovation Center,SantenInc.,Emeryville,CA,United States
FatimaMuili OphthalmicPharmacology ResearchLaboratory,Departmentof PharmaceuticalSciences,JoanM.Lafleur CollegeofPharmacyandHealthSciences, TexasSouthernUniversity,Houston,TX, UnitedStates
DarrylNarcisse NanoscopeTechnologiesLLC, Arlington,TX,UnitedStates
WeiYanNg SingaporeEyeResearchInstitute, Singapore,Singapore
KaluK.Ngele OphthalmicPharmacology ResearchLaboratory,Departmentof PharmaceuticalSciences,JoanM.Lafleur CollegeofPharmacyandHealthSciences, TexasSouthernUniversity,Houston,TX, UnitedStates
YaFatouNjie-Mbye Ophthalmic PharmacologyResearchLaboratory, DepartmentofPharmaceuticalSciences,Joan M.LafleurCollegeofPharmacyandHealth Sciences,TexasSouthernUniversity, Houston,TX,UnitedStates
SunnyE.Ohia OphthalmicPharmacology ResearchLaboratory,Departmentof PharmaceuticalSciences,JoanM.Lafleur CollegeofPharmacyandHealthSciences, TexasSouthernUniversity,Houston,TX, UnitedStates
OdochiOhia-Nwoko Departmentof PharmacologicalandPharmaceutical Sciences,CollegeofPharmacy,Universityof Houston,Houston,TX,UnitedStates
Shin-ichiOhnuma UCLInstituteof Ophthalmology,UniversityCollegeLondon, London,UnitedKingdom
AnthoniaOkolie OphthalmicPharmacology ResearchLaboratory,Departmentof PharmaceuticalSciences,JoanM.Lafleur CollegeofPharmacyandHealthSciences, TexasSouthernUniversity,Houston,TX, UnitedStates
CatherineA.Opere DepartmentofPharmacy Sciences,SchoolofPharmacyandHealth Professions,CreightonUniversity,Omaha, NE,UnitedStates;SchoolofPharmacyand HealthProfessions,CreightonUniversity, Omaha,NE,UnitedStates
LeonardPinchuk BiomedicalEngineering Department,UniversityofMiami,Miami,FL, UnitedStates
AkashRaola DepartmentofPharmacology andNeuroscienceandtheNorthTexasEye ResearchInstitute,UniversityofNorthTexas HealthScienceCenter,FortWorth,TX, UnitedStates
OmarSadruddin SantenInc.,Emeryville,CA, UnitedStates
NajamA.Sharif GlobalAlliancesandExternal Research,OphthalmologyInnovationCenter, SantenInc.,Emeryville,CA,UnitedStates; DepartmentofPharmacySciences,Creighton University,Omaha,NE,UnitedStates; SingaporeEyeResearchInstitute(SERI), Singapore,Singapore;Duke-National UniversityofSingaporeMedicalSchool, Singapore;DepartmentofSurgery&Cancer, ImperialCollegeofScienceandTechnology, St.Mary’sCampus,London,United Kingdom;DepartmentofPharmaceutical Sciences,CollegeofPharmacyandHealth Sciences,TexasSouthernUniversity, Houston,TX,UnitedStates;Departmentof PharmacologyandNeuroscience,University ofNorthTexasHealthSciencesCenter,Fort Worth,TX,UnitedStates;Instituteof Ophthalmology,UniversityCollegeLondon, London,UnitedKingdom
KeiichiShibagaki VitreousandRetina TherapeuticArea,OphthalmologyInnovation Center,SantenInc.,Emeryville,CA,United States
YouichiShinozaki Departmentof Neuropharmacology,InterdisciplinaryGraduate SchoolofMedicine,UniversityofYamanashi, Chuo,Japan;GLIACenter,Interdisciplinary
GraduateSchoolofMedicine,Universityof Yamanashi,Chuo,Japan
OnkarN.Singh VP,CMC/Mfg/TechOps, AlentiaTherapeutics,FortWorth,TX,United States
W.DanielStamer Departmentof Ophthalmology,DukeUniversity,Durham, NC,UnitedStates
AllisonStradiotto DepartmentofSurgery (Ophthalmology),SchoolofMedicine, CreightonUniversity,Omaha,NE,United States
JillSturdivant AeriePharmaceuticals, Durham,NC,UnitedStates
MasanaoToshimori VitreousandRetina TherapeuticArea,OphthalmologyInnovation Center,SantenInc.,Emeryville,CA,United States
SamYacoub DepartmentofPharmacology andNeuroscienceandtheNorthTexasEye ResearchInstitute,UniversityofNorthTexas HealthScienceCenter,FortWorth,TX, UnitedStates
DariushYalzadeh DepartmentofPharmacy Sciences,SchoolofPharmacyandHealth Profession,CreightonUniversity,Omaha, NE,UnitedStates;DepartmentofEcology andEvolutionaryBiology,Universityof CaliforniaLosAngeles,LosAngeles,CA, UnitedStates
TimothyE.Yap TheImperialCollege OphthalmicResearchGroup(ICORG), ImperialCollegeLondonNW,London, UnitedKingdom;TheWesternEyeHospital, ImperialCollegeHealthcareNHSTrust (ICHNT),LondonNW,UnitedKingdom
BenjaminR.Yerxa FoundationFighting Blindness,Columbia,MD,UnitedStates
GulabZode DepartmentofPharmacologyand NeuroscienceandtheNorthTexasEye ResearchInstitute,UniversityofNorthTexas HealthScienceCenter,FortWorth,TX, UnitedStates
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Preface
Eyesightisavitalsensewemustcherish, protect,preserve,andappreciate.An understandingofthepharmacological actionsofdrugsactingontheeyerequires bothstudentsandhealthcarepractitioners tolearnadditionalprinciplesinbasicand clinicalsciencesthatareuniquetothis organ.Asasensoryorgan,theeyeis relativelyinaccessibletothesystemic circulationduetotheblood-vitreous, blood-aqueous,andblood-retinalbarriers. Consequently,atopicalocularrouteof administrationofdrugstotreatvariouseye diseasesisrequired.Thisposesmanychallengesasdeliveryofthetherapeuticcompoundstotheirsite(s)ofactionwithinthe eyeisdeterminedbymanyfactorsincludingphysicochemicalpropertiesofthemoleculesandtheirpharmacokinetics.The pharmacodynamicaspectsofdrugefficacy arethendictatedbytheambientdrugconcentrationachievedattheactivesite,the fullorpartialengagementwiththetarget receptor/enzyme/ion-channel,andthe activationorinhibitionofthesignaltransductionpathwaythatultimatelyresultsin thebiologicalresponserequired.
Thefirstfourchaptersofthehandbook provideinformation,inabriefmanner,the basicanatomy,physiology,biochemistry, andpathologyoftheeye,anditstargetsfor drugaction.Additionally,newdrug
discoveryprocesses,differentoculardrug formulations,andnoveldrugdeliverysystemsandtheprinciplesofpharmacokineticsarecoveredinthesechapters.Thenext sixchaptersofthehandbookaredirected atthepharmacotherapyofseveraldiseases withbothbasicandclinicalsciencesof eachdiseasecoveredintheirrespectivesections.Currenttrendsintherapy,including theuseofmolecularbiologicalapproaches andnoveldevices,arealsodiscussedfor therelevantdiseasestates.In Chapter12, theocularside-effectsofdrugsadministeredforthetreatmentofnonoculardiseasesarediscussed.Finally, Chapter13 is focusedonfuturetherapeuticapproaches andresearchinnovationsthatwillformthe basisofinnovativetreatmentsofeyediseases.Weanticipatethatthecontentsofthe handbookwillmeettheneedsofstudents inthehealthcaredisciplines(e.g.,nursing, pharmacy,ophthalmologyandoptometry, medicine)andresearchersandcliniciansin optometryandocularsciences.Bothstudentsandpractitionerswillfindthebook usefulasaprimaryandsecondarysource ofreferenceforup-to-dateinformation abouteyediseases,anddrugsanddevices thatareimportantfortheirtreatments.We hopethatourhumblecontributionspave thewayforfutureresearchanddiscovery ofnovelmodalitiesthatcanhelpcombat
thesignsandsymptomsofoculardisorders andpreserveeyesightofthoseafflicted withsuchmaladies.
SunnyE.Ohia
OphthalmicPharmacology ResearchLaboratory, DepartmentofPharmaceuticalSciences, JoanM.LafleurCollegeofPharmacyandHealth Sciences,TexasSouthernUniversity,Houston, TX,UnitedStates
NajamA.Sharif
GlobalAlliancesandExternalResearch, OphthalmologyInnovationCenter, SantenInc.,Emeryville,CA,UnitedStates DepartmentofPharmacySciences,Creighton University,Omaha,NE,UnitedStates SingaporeEyeResearchInstitute(SERI), Singapore,Singapore Duke-NationalUniversityofSingapore MedicalSchool,Singapore DepartmentofSurgery&Cancer, ImperialCollegeofScienceandTechnology, St.Mary’sCampus,London,UnitedKingdom DepartmentofPharmaceuticalSciences, CollegeofPharmacyandHealthSciences, TexasSouthernUniversity, Houston,TX,UnitedStates DepartmentofPharmacologyandNeuroscience, UniversityofNorthTexasHealthSciencesCenter, FortWorth,TX,UnitedStates InstituteofOphthalmology,UniversityCollege London,London,UnitedKingdom
Acknowledgments
Thetimeandeffortneededtowritea handbookwithacomprehensiveapproach thatcoverstheetiologyofnumerousophthalmicdiseasesanddrugsandrelevant technologicaldevicestotreatthem involvedreachingouttocolleaguesworldwidewithexpertiseinbasicandclinical sciencesoftheeye.Weherebyacknowledgethecontributionsofover50basic scientistsandclinicianswhogenerously contributedtothesuccessofthishandbook bytheirwillingnesstowritethedifferent sectionsandchapters.Wealsoacknowledgetheconstantsupportandunderstandingofourfamiliesduringthenumerous
hoursthatwehavespentwritingvarious chaptersandeditingthecontentsofthis handbook.Specifically,ourparents,wives, andchildrenarethankedfortheirenduring loveandsupportwithoutwhichnoneof ourresearchandscholarlyworkwould havebeenpossible.Wearegratefulforthe kindandgeneroussupportofErinHillParksandTracyTufagaandherothercolleaguesatElsevierthroughoutthechapter submissions,arrangement,andpublishing process.WealsothankElsevierforsponsoringandpublishingthisbook.
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Theeyeasatargetfordrugsand othertreatmentmodalities
SUBCHAPTER
1.1
Anatomyandpathology
MartinaC.Herwig-CarlandKarinU.Loeffler DepartmentofOphthalmology,DivisionofOphthalmicPathology,UniversityHospitalBonn, Bonn,Germany
Introduction
Theeyestartsdevelopingatday22,anditsmaturationisnotfullycompleteduntil childhood.Whilefromamacroscopicview,thefetaleyelooksalreadyverycomplete (Fig.1.1.1A),andinparticular,theretinaanditsvasculatureaswellasthechamberangle arerelativelyimmatureintheearlyfetalstageandcontinuetodevelopduringthefetal lifeand—regardingthemacula—beyond(VerdijkandHerwig-Carl,2020).
Theaverageadulteyemeasures24mmindiameter,andtheclearcorneameasures11.8 (horizontal) 3 11.2(vertical)mm(Fig.1.1.1B)(Augusteynetal.,2012).Theeyeispredominantlygrowingduringfetaldevelopment,andtheoculargrowthisceasingduringthe firstyear(VerdijkandHerwig-Carl,2020;Augusteynetal.,2012)butcan—forexample,in myopia—continuetoenlargeuntilthethirddecade.
