- •Foreword
- •List of contributors
- •Preface
- •Dedication and Acknowledgments
- •Evolving knowledge in pharmacologic treatments
- •MEDICAL TREATMENT
- •VERTEPORFIN
- •ANTI-VEGF TREATMENT
- •OTHER MEDICAL TREATMENTS
- •“PLAYERS” IN OCULAR TREATMENT
- •THE DRUG
- •ROUTE OF ADMINISTRATION
- •Eye drops
- •Soluble ophthalmic drug inserts
- •Ion drug exchange
- •Intravitreal injections
- •Systemic administration
- •Sustained drug delivery system
- •Intraocular implants
- •Microparticles and nanoparticles
- •Liposomes
- •Encapsulated cell technology (ECT)
- •Iontophoresis
- •REFERENCES
- •SECTION 1: Basic Sciences in Retina
- •Retinal anatomy and pathology
- •INTRODUCTION
- •KEY CONCEPTS AND FUNDAMENTALS
- •NORMAL RETINAL ANATOMY
- •RETINAL PATHOLOGY
- •Congenital abnormalities
- •Dystrophies
- •Degenerations
- •Vascular diseases
- •Toxicities
- •Inflammatory diseases
- •Neoplasms
- •Retinal detachment
- •Trauma
- •Involvement of systemic diseases
- •SUMMARY AND KEY POINTS
- •REFERENCES
- •Retinal biochemistry, physiology, and cell biology
- •INTRODUCTION
- •VITREOUS BIOCHEMISTRY
- •VITREOUS DEGENERATION WITH AGING
- •PHYSIOLOGICAL AND PATHOLOGICAL CHANGES IN THE VITREORETINAL INTERFACE
- •BLOOD–RETINAL BARRIER
- •TIGHT JUNCTIONS
- •BLOOD–RETINA BARRIER DISRUPTION
- •MECHANISMS OF RETINAL ARTERIOLAR CALIBER CHANGES
- •MECHANISMS OF RETINAL VENULAR CALIBER CHANGES
- •MACULAR PIGMENTS
- •FUNCTIONS OF MACULAR PIGMENTS
- •Antioxidant
- •Optical filter
- •VISUAL CYCLE
- •RETINOID CYCLE
- •Outer segment of photoreceptors
- •Retinal pigment epithelium
- •Re-entry into the outer segment
- •Chaperones
- •PHOTOTRANSDUCTION
- •Activation
- •Inactivation
- •RETINAL PIGMENT EPITHELIUM AND LIPOFUSCIN
- •RETINAL PIGMENT EPITHELIUM
- •LIPOFUSCIN
- •Formation of lipofuscin
- •Lipofuscin and RPE atrophy
- •Stargardt’s disease and lipofuscin
- •Age-related macular degeneration and lipofuscin
- •MATRIX BIOLOGY
- •STRUCTURAL COMPOSITION OF THE BRUCH’S MEMBRANE
- •MACROSCOPIC CHANGES OF THE BRUCH’S MEMBRANE
- •CELL BIOLOGY OF BRUCH’S MEMBRANE
- •LIPID ACCUMULATION
- •MATRIX DYSREGULATION
- •MATRIX METALLOPROTEINASES
- •PHARMACOTHERAPY IMPLICATIONS
- •REFERENCES
- •INTRODUCTION
- •PROMOTERS OF ANGIOGENESIS
- •VEGF in physiologic and pathologic angiogenesis
- •Investigational approaches to VEGF inhibition in ocular neovascularization
- •RNA interference
- •Soluble VEGFR fusion protein: VEGF-Trap
- •Anecortave acetate
- •PLATELET-DERIVED GROWTH FACTOR
- •FIBROBLAST GROWTH FACTOR 2 (FGF2)
- •TUMOR NECROSIS FACTOR-α (TNF-α)
- •EPHS AND EPHRINS
- •NOTCH
- •ANGIOPOIETINS
- •Angiopoietin 1
- •Angiopoietin 2
- •ERYTHROPOIETIN
- •MATRIX METALLOPROTEINASES
- •INTEGRINS
- •COMPONENTS OF THE COMPLEMENT CASCADE
- •INHIBITORS OF ANGIOGENESIS
- •PIGMENT EPITHELIUM-DERIVED FACTOR
- •SOLUBLE VEGF RECEPTOR 1
- •VEGFXXXb ISOFORMS
- •COMPLEMENTARY REGULATORY PROTEIN C59
- •TRYPTOPHANYL-tRNA SYNTHASE FRAGMENT
- •OTHER INHIBITORS
- •SUMMARY
- •REFERENCES
- •Ocular immunity and inflammation
- •INTRODUCTION
- •HISTORY
- •KEY CONCEPTS AND FUNDAMENTALS IN MOLECULAR BIOLOGY AND BIOCHEMISTRY
- •INNATE IMMUNITY
- •ADAPTIVE IMMUNITY
- •MECHANISMS OF PATHOGENESIS
- •NONINFECTIOUS POSTERIOR AND PANUVEITIS
- •INFECTIOUS RETINITIS AND CHOROIDITIS
- •AGE-RELATED MACULAR DEGENERATION
- •DIABETIC RETINOPATHY
- •SUMMARY AND KEY POINTS
- •REFERENCES
- •INTRODUCTION
- •HISTORY
- •KEY CONCEPTS IN COMPLEMENT BIOLOGY
- •SUMMARY
- •REFERENCES
- •Genetics of retinal disease
- •INTRODUCTION
- •HISTORY OF RETINAL GENE DISCOVERY
- •KEY CONCEPTS AND FUNDAMENTS OF GENETIC METHODS IN THE STUDY OF RETINAL DISEASE
- •GENETICS: ILLUMINATING MECHANISMS OF PATHOGENESIS, REVEALING COMPLEXITY
- •RP: A “COMPLEX” MONOGENIC DISEASE
- •SHEDDING LIGHT ON AMD
- •DELIVERY OF GENES TO TARGET PATHOGENIC PATHWAYS
- •GENE-INDEPENDENT THERAPY
- •SUMMARY: THE FUTURE IS BRIGHT
- •REFERENCES
- •SECTION 2: Animal Models and Routes for Retinal Drug Delivery
- •Vitamins and supplements for age-related macular degeneration
- •INTRODUCTION
- •HISTORY
- •KEY CONCEPTS AND PHARMACOLOGY OF CURRENT DIETARY SUPPLEMENTS
- •EPIDEMIOLOGIC DATA OF ASSOCIATION OF FAT AND ω-3 LCPUFAs WITH AMD
- •AVAILABLE SUPPLEMENTS FOR MACULAR DEGENERATION
- •IMPLICATIONS OF RETINAL SUPPLEMENT PHARMACOLOGY
- •FUTURE DIRECTIONS: AREDS2
- •SUMMARY AND KEY POINTS
- •REFERENCES
- •Ocular pharmacokinetic, drug bioavailability, and intraocular drug delivery systems
- •INTRODUCTION
- •INTRAVITREAL ADMINISTRATION
- •OCULAR PHARMACOKINETICS
- •TOPICAL FORMULATIONS
- •CONVENTIONAL FORMULATIONS
- •INTRAOCULAR DRUG DELIVERY SYSTEMS
- •NONBIODEGRADABLE IMPLANTS
- •INTRAOCULAR BIODEGRADABLE DRUG DELIVERY SYSTEMS
- •ACKNOWLEDGMENTS
- •REFERENCES
- •INTRODUCTION
- •THE RATIONALE FOR INTRAVITREAL DRUG DELIVERY
- •HISTORY
- •KEY CONCEPTS AND FUNDAMENTAL POINTS IN RETINAL DRUG DELIVERY
- •STRATEGIES AND IMPLICATIONS FOR RETINAL PHARMACOTHERAPY
- •PREOPERATIVE PREPARATION
- •PROPHYLAXIS OF ENDOPHTHALMITIS: LOCAL DISINFECTION AND TOPICAL ANTIBIOTIC THERAPY
- •LOCAL TOPICAL ANESTHESIA
- •SURGICAL TECHNIQUES FOR RETINAL DRUG DELIVERY
- •THE PROCEDURE AND RECOMMENDED TECHNIQUE
- •COMPLICATIONS WITH THE ROUTE FOR DRUG DELIVERY
- •OCULAR COMPLICATIONS
- •PHARMACOKINETICS AND CLEARANCE OF INTRAVITREAL DRUGS
- •PHARMACOKINETICS OF INTRAVITREAL CRYSTALLINE TRIAMCINOLONE ACETONIDE
- •CLINICAL EXPERIENCE AND RESULTS IN VITRECTOMIZED, AIR-FILLED, OR SILICONE OIL EYES
- •VITRECTOMIZED EYES
- •Silicone oil tamponade
- •Gas tamponade
- •PREOPERATIVE DRUG APPLICATIONS
- •INTRAOPERATIVE DRUG APPLICATIONS
- •POSTOPERATIVE DRUG APPLICATIONS
- •SUMMARY AND KEY POINTS
- •REFERENCES
- •INTRODUCTION
- •HISTORY
- •KEY CONCEPTS
- •ANIMAL MODELS
- •DRUG DELIVERY MODALITIES
- •TOPICAL DRUG DELIVERY
- •TRANSSCLERAL DRUG DELIVERY
- •SUPRACHOROIDAL DRUG DELIVERY
- •INTRAVITREAL GAS-PHASE NANOPARTICLE DRUG DELIVERY
- •SUMMARY AND KEY POINTS
- •ACKNOWLEDGMENT
- •REFERENCES
- •INTRODUCTION
- •HISTORY
- •KEY CONCEPTS AND FUNDAMENTAL POINTS IN SUSTAINED-RELEASE DRUG DELIVERY
- •EXISTING SUSTAINED-RELEASE DRUG DEVICES
- •BIODEGRADABLE POLYMER IMPLANTS
- •LIPOSOME ENCAPSULATION
- •CELLULAR ENCAPSULATION
- •THE FUTURE
- •SUMMARY
- •ACKNOWLEDGMENT
- •REFERENCES
- •INTRODUCTION
- •PERMEATION BARRIERS AND ANATOMICAL CONSIDERATIONS
- •THEORETICAL BACKGROUND
- •CYCLODEXTRINS
- •ANIMAL TESTING OF ROUTES OF DRUG DELIVERY
- •SUMMARY AND KEY POINTS
- •REFERENCES
- •Thermo-sensitive hydrogels
- •INTRODUCTION
- •DELIVERY CHARACTERISTICS
- •POTENTIAL DELIVERY SITE
- •TOXICITY TESTING
- •FUTURE DIRECTION
- •SUMMARY AND KEY POINTS
- •REFERENCES
- •Retina and ocular toxicity to ocular application of drugs
- •INTRODUCTION
- •HISTORY
- •MAJOR CLASSES OF DRUGS AND THEIR SAFETY PROFILE AFTER LOCAL OCULAR APPLICATION FOR RETINA THERAPY
- •CORTICOSTEROIDS
- •ANTIBIOTICS
- •NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
- •ENZYMES AND FIBRINOLYTICS
- •MISCELLANEOUS ANTI-INFLAMMATORY AND ANTIANGIOGENIC AGENTS
- •Summary and Key points
- •ACKNOWLEDGMENTS
- •REFERENCES
- •INTRODUCTION
- •KEY CONCEPTS AND FUNDAMENTALS
- •PHARMACOLOGY, BIOCHEMISTRY, AND TYPE OF IMPACT ON THE RETINA
- •DISRUPTION OF THE RETINA AND RETINAL PIGMENT EPITHELIUM
- •Phenothiazines
- •Thioridazine
- •Chlorpromazine
- •Chloroquine derivatives
- •Chloroquine
- •Hydroxychloroquine
- •Quinine sulfate
- •Clofazimine
- •2′,3′-dideoxyinosine (DDI)
- •Deferoxamine
- •Corticosteroid preparations
- •Cisplatin and BCNU (carmustine)
- •Potassium iodate
- •VASCULAR DAMAGE OR OCCLUSION
- •Quinine sulfate
- •Cisplatin and BCNU (carmustine)
- •Talc
- •Oral contraceptives
- •Aminoglycoside antibiotics
- •Interferon
- •Miscellaneous agents
- •CYSTOID MACULAR EDEMA AND RETINAL EDEMA/FOLDS
- •CYSTOID MACULAR EDEMA
- •Epinephrine and dipivefrin
- •Nicotinic acid
- •Prostaglandin analogues
- •Retinal edema/folds
- •Sulfa antibiotics, acetazolamide, ethoxyzolamide, chlorthalidone, hydrochlorothiazide, triamterene, metronidazole
- •Topiramate
- •CRYSTALLINE RETINOPATHY
- •TAMOXIFEN
- •CANTHAXANTHINE
- •METHOXYFLURANE
- •TALC
- •NITROFURANTOIN
- •UVEITIS
- •RIFABUTIN
- •CIDOFOVIR
- •LATANOPROST
- •CARDIAC GLYCOSIDES
- •SILDENAFIL
- •METHANOL
- •VIGABATRIN
- •SUMMARY AND KEY POINTS
- •REFERENCES
- •INTRODUCTION
- •DISEASE PREVALENCE AND INFLUENCE
- •RISK FACTORS
- •ETIOLOGY/PATHOGENESIS
- •SIGNS AND SYMPTOMS
- •TREATMENT OPTIONS
- •VITAMIN C
- •CAROTENOIDS
- •VITAMIN E
- •MINERALS
- •SUMMARY AND KEY POINTS
- •REFERENCES
- •Neovascular age-related macular degeneration
- •DISEASE PREVALENCE AND INFLUENCE
- •RISK FACTORS
- •ETIOLOGY/PATHOGENESIS
- •NATURAL HISTORY
- •NONPHARMACOLOGIC THERAPIES
- •PHARMACOLOGIC THERAPIES
- •PDT WITH VERTEPORFIN
- •PEGAPTANIB
- •RANIBIZUMAB
- •BEVACIZUMAB
- •COMBINATION THERAPY
- •TREATMENTS UNDER INVESTIGATION
- •SUMMARY AND KEY POINTS
- •REFERENCES
- •Diabetic retinopathy and diabetic macular edema
- •INTRODUCTION
- •DIABETIC RETINOPATHY PREVALENCE
- •RISK FACTORS
- •ETIOLOGY AND PATHOGENESIS
- •SIGNS AND SYMPTOMS
- •TREATMENT OPTIONS
- •SUMMARY AND KEY POINTS
- •REFERENCES
- •Retinal vein occlusion
- •INTRODUCTION
- •DISEASE PREVALENCE
- •RISK FACTORS
- •PATHOGENESIS
- •CENTRAL RETINAL VEIN OCCLUSION
- •BRANCH RETINAL VEIN OCCLUSION
- •TREATMENT OPTIONS
- •CENTRAL RETINAL VEIN OCCLUSION
- •BRANCH RETINAL VEIN OCCLUSION
- •TREATMENT OUTCOMES AND PROGNOSIS
- •CENTRAL RETINAL VEIN OCCLUSION
- •TISSUE PLASMINOGEN ACTIVATOR (tPA)
- •CORTICOSTEROIDS
- •BEVACIZUMAB
- •OTHER MEDICATIONS
- •Ranimizumab
- •Coumadin (warfarin)
- •Urokinase
- •Troxerutin
- •Ticlodipine
- •Pentoxifylline
- •Hemodilution
- •Laser treatment
- •Chorioretinal venous anastomosis
- •SURGICAL TREATMENT OF CRVO
- •Radial optic neurotomy (ron)
- •Branch retinal vein occlusion
- •Corticosteroids
- •Bevacizumab
- •Ranimizumab
- •Laser treatment
- •SURGICAL TREATMENT OF BRVO
- •SUMMARY AND KEY POINTS
- •REFERENCES
- •Retinal detachment and proliferative vitreoretinopathy
- •INTRODUCTION
- •INCIDENCE OF RETINAL DETACHMENT
- •ETIOLOGY AND RISK FACTORS FOR RETINAL DETACHMENT
- •RISK FACTORS FOR PROLIFERATIVE VITREORETINOPATHY
- •SIGNS, SYMPTOMS, AND DIAGNOSIS
- •TREATMENT OPTIONS
- •PROGNOSIS WITH THE VARIOUS TREATMENT OPTIONS
- •ADJUNCTIVE THERAPIES
- •SUMMARY AND KEY POINTS
- •REFERENCES
- •Posterior Uveitis
- •INTRODUCTION
- •DISEASE PREVALENCE AND INFLUENCE
- •RISK FACTORS
- •PATHOGENESIS
- •SPECIFIC DISEASES: DIAGNOSIS AND PHARMACOTHERAPY
- •ADAMANTIADES–BEHÇET DISEASE
- •Diagnostic features
- •Treatment modalities
- •BIRDSHOT RETINOCHOROIDOPATHY
- •Diagnostic features
- •Treatment modalities
- •Treatment modalities
- •SARCOIDOSIS
- •Diagnostic features
- •Treatment modalities
- •SERPIGINOUS CHOROIDOPATHY
- •Diagnostic features
- •Treatment modalities
- •VOGT–KOYANAGI–HARADA SYNDROME
- •Diagnostic features
- •Treatment modalities
- •SYMPATHETIC OPHTHALMIA
- •Diagnostic features
- •Treatment modalities
- •SUMMARY AND KEY POINTS
- •REFERENCES
- •INTRODUCTION
- •DISEASE PREVALENCE
- •RISK FACTORS
- •MYOPIA
- •PRESUMED OCULAR HISTOPLASMOSIS SYNDROME
- •OTHER INFLAMMATORY CAUSES
- •ANGIOID STREAKS
- •IDIOPATHIC CNV
- •ETIOLOGY AND PATHOGENESIS
- •DIAGNOSIS AND ANCILLARY TESTING
- •MYOPIA
- •PRESUMED OCULAR HISTOPLASMOSIS SYNDROME
- •ANGIOID STREAKS
- •INFLAMMATORY CAUSES
- •DIFFERENTIAL DIAGNOSIS
- •CLINICAL SIGNS AND SYMPTOMS
- •MYOPIA
- •PRESUMED OCULAR HISTOPLASMOSIS SYNDROME
- •ANGIOID STREAKS
- •INFLAMMATORY CAUSES
- •TREATMENT
- •PHOTODYNAMIC THERAPY
- •SURGICAL THERAPY
- •ANTIANGIOGENIC THERAPY
- •SUMMARY AND KEY POINTS
- •REFERENCES
- •INTRODUCTION
- •DISEASE INCIDENCE
- •RISK FACTORS
- •ETIOLOGY/PATHOGENESIS
- •SIGNS AND SYMPTOMS
- •OCULAR
- •SYSTEMIC
- •TREATMENT OPTIONS
- •SUMMARY AND KEY POINTS
- •ACKNOWLEDGMENTS
- •REFERENCES
- •Retinopathy of prematurity
- •INTRODUCTION
- •DISEASE PREVALENCE AND INFLUENCE
- •RISK FACTORS
- •ETIOLOGY/PATHOGENESIS
- •ABNORMAL RETINAL VASCULARIZATION IN ROP
- •ROLE OF GROWTH FACTORS IN ROP
- •DIAGNOSIS AND ANCILLARY TESTING/DIFFERENTIAL DIAGNOSIS
- •SIGNS AND SYMPTOMS
- •CLASSIFICATION OF RETINOPATHY OF PREMATURITY
- •TREATMENT OPTIONS FOR RETINOPATHY OF PREMATURITY
- •CRYOTHERAPY AND LASER THERAPY
- •INTRAVITREAL ANTI-VEGF THERAPY FOR ROP
- •Rationale for Treatment
- •Injection Technique
- •Patients
- •Results
- •Other Reported Results
- •Concerns with Intravitreal Anti-VEGF Therapy for ROP
- •Ocular complications
- •Systemic Complications
- •Vitrectomy
- •SUMMARY
- •REFERENCES
- •Idiopathic macular telangiectasia
- •INTRODUCTION
- •THERAPY
- •NONPROLIFERATIVE STAGE
- •PROLIFERATIVE STAGE
- •SUMMARY AND KEY POINTS
- •REFERENCES
- •Neovascular glaucoma
- •INTRODUCTION
- •DISEASE PREVALENCE AND INFLUENCE
- •RISK FACTORS
- •ETIOLOGY/PATHOGENESIS
- •CENTRAL RETINAL VEIN OCCLUSION
- •DIABETIC RETINOPATHY
- •DIABETIC NEOVASCULAR GLAUCOMA
- •CAROTID ARTERY OCCLUSIVE DISEASE
- •CENTRAL RETINAL ARTERY OCCLUSION
- •INTRAOCULAR TUMORS
- •Malignant melanoma
- •Retinoblastoma
- •MISCELLANEOUS CAUSES
- •DIAGNOSIS AND ANCILLARY TESTING
- •DIFFERENTIAL DIAGNOSIS
- •SIGNS AND SYMPTOMS
- •TREATMENT OPTIONS
- •TREATMENT OF THE UNDERLYING DISEASE ASSOCIATED WITH NVG
- •Central retinal vein occlusion
- •Diabetic retinopathy
- •Carotid artery occlusive disease
- •Central retinal artery occlusion
- •PHARMACOLOGIC THERAPIES
- •Medical treatment to control high IOP
- •Anti-VEGF therapy
- •Corticosteroid therapy
- •Photodynamic therapy
- •SUMMARY AND KEY POINTS
- •REFERENCES
- •INTRODUCTION
- •SPECIFIC DISEASES
- •RETINITIS PIGMENTOSA
- •Nutrients and retinitis pigmentosa
- •Cystoid Macular Edema (CME) associated with RP
- •Ciliary Neurotrophic Factor and retinitis pigmentosa
- •REFSUM’S DISEASE
- •Treatment
- •Dietary restriction
- •Plasmapheresis
- •GYRATE ATROPHY
- •Treatment
- •Arginine-restricted diet
- •Vitamin B6 supplementation
- •ABETALIPOPROTEINEMIA (BASSEN–KORNZWEIG SYNDROME)
- •Treatment
- •LEBER CONGENITAL AMAUROSIS
- •Treatment
- •RPE65 gene therapy
- •X-LINKED JUVENILE RETINOSCHISIS
- •Treatment
- •SUMMARY AND KEY POINTS
- •REFERENCES
- •SECTION 4: Drugs and Mechanisms in Retinal Diseases
- •Nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of retinal diseases
- •KEY FEATURES
- •INTRODUCTION AND HISTORY
- •PHARMACOLOGY, DRUG MECHANISM, AND EFFECTS
- •DICLOFENAC
- •KETOROLAC
- •NEVANAC
- •BROMFENAC
- •DICLOFENAC
- •KETOROLAC
- •NEPAFENAC
- •BROMFENAC
- •CONTRAINDICATIONS, COMPLICATIONS, AND TOXICITY
- •SUMMARY AND KEY POINTS
- •ACKNOWLEDGMENTS
- •REFERENCES
- •KEY FEATURES
- •INTRODUCTION
- •PHARMACOLOGY
- •STRUCTURE
- •METABOLISM
- •Dexamethasone
- •Fluocinolone
- •CYSTOID MACULAR EDEMA
- •DIABETIC MACULAR EDEMA
- •RETINAL VEIN OCCLUSION
- •EXUDATIVE AGE-RELATED MACULAR DEGENERATION (AMD)
- •Raised intraocular pressure
- •Infectious, sterile, and pseudoendophthalmitis associated with triamcinolone acetonide
- •Cataract
- •Retinal detachment
- •FUTURE CONSIDERATIONS AND ONGOING STUDIES
- •THE SCORE STUDY
- •STEROID-SUSTAINED RELEASE DEVICES
- •The STRIDE study
- •FLUOCINOLONE ACETONIDE DEVICE
- •NEW-GENERATION FLUOCINOLONE DEVICE
- •SUMMARY AND KEY POINTS
- •REFERENCES
- •Anecortave acetate
- •KEY FEATURES
- •INTRODUCTION AND HISTORY
- •PHARMACOLOGY
- •DRUG MECHANISM
- •DRUG EFFECTS IN RETINAL DISEASES
- •PRECLINICAL STUDIES
- •Retinopathy of prematurity
- •Intraocular tumors
- •Choroidal neovascularization
- •CLINICAL STUDIES
- •Exudative AMD
- •Other diseases
- •EFFICACY AND COMPARISON WITH OTHER AGENTS
- •CONTRAINDICATIONS
- •OCULAR COMPLICATIONS AND TOXICITY
- •SYSTEMIC COMPLICATIONS AND TOXICITY
- •DRUG INTERACTIONS
- •SUMMARY AND KEY POINTS
- •ACKNOWLEDGMENTS
- •REFERENCES
- •KEY FEATURES
- •INTRODUCTION AND HISTORY
- •PHARMACOLOGY
- •DRUG MECHANISM
- •DRUG USE IN RETINAL DISEASES
- •AGE-RELATED MACULAR DEGENERATION
- •DIABETIC RETINOPATHY
- •RETINAL VEIN OCCLUSION (RVO)
- •UVEITIC CYSTOID MACULAR EDEMA (CME)
- •RETINOPATHY OF PREMATURITY (ROP)
- •RETINAL TELANGIECTASIAS
- •NEOVASCULAR GLAUCOMA (NVG)
- •OTHERS
- •CONTRAINDICATIONS
- •OCULAR COMPLICATIONS AND TOXICITY
- •SYSTEMIC COMPLICATION AND TOXICITY
- •DRUG INTERACTIONS
- •SUMMARY AND KEY POINTS
- •REFERENCES
- •KEY FEATURES
- •INTRODUCTION AND HISTORY
- •PHARMACOLOGY
- •PHARMACOLOGICAL DESIGN
- •PHARMACOKINETICS
- •PHARMACODYNAMICS
- •DRUG MECHANISM
- •DRUG USE IN RETINAL DISEASES
- •EFFICACY
- •EFFICACY IN AMD
- •EFFICACY IN OTHER RETINAL DISEASES
- •CONTRAINDICATIONS
- •OCULAR COMPLICATIONS AND TOXICITY
- •DRUG INTERACTIONS
- •SUMMARY AND KEY POINTS
- •REFERENCES
- •Pathophysiology of vascular endothelial growth factor and other angiogenic molecules
- •KEY FEATURES
- •INTRODUCTION
- •BIOLOGICAL EFFECTS OF VEGF-A
- •VEGF-A ISOFORMS
- •VEGF RECEPTORS
- •ROLE OF VEGF-A IN INTRAOCULAR NEOVASCULAR SYNDROMES
- •INTRAVITREAL ANTI-VEGF THERAPY FOR NEOVASCULAR AMD: PEGAPTANIB, RANIBIZUMAB AND BEVACIZUMAB
- •OTHER ANTI-VEGF THERAPIES IN CLINICAL DEVELOPMENT FOR AMD
- •OTHER ANGIOGENIC FACTORS
- •FIBROBLAST GROWTH FACTOR FAMILY
- •PLACENTAL GROWTH FACTOR
- •DELTA-LIKE LIGAND 4
- •SUMMARY AND KEYPOINTS
- •REFERENCES
- •KEY FEATURES
- •INTRODUCTION
- •TUMOR NECROSIS FACTOR-ALPHA ANTAGONISTS
- •INFLIXIMAB (REMICADE)
- •Pharmacology and mechanism
- •Systemic indications for infliximab
- •Ophthalmic indications for infliximab
- •Contraindications
- •Ocular complications and toxicity
- •Systemic complications and toxicity
- •Drug interactions
- •Summary
- •ADALIMUMAB (HUMIRA)
- •Pharmacology and mechanism
- •Systemic indications
- •Ophthalmic indications
- •Contraindications
- •Ocular toxicity
- •Systemic toxicity
- •Drug interactions
- •Summary
- •ETANERCEPT (ENBREL)
- •Pharmacology and mechanism
- •Systemic indications
- •Ophthalmic indications
- •Contraindications
- •Ocular toxicity
- •Systemic toxicity
- •Drug interactions
- •Summary
- •INTERLEUKIN-2 RECEPTOR ANTAGONIST
- •DACLIZUMAB (ZENAPAX)
- •Pharmacology and mechanism
- •Systemic indication
- •Ophthalmic indications
- •Contraindications
- •Ocular toxicity
- •Systemic toxicity
- •Drug interactions
- •Summary
- •OTHER BIOLOGIC AGENTS
- •SUMMARY AND KEY POINTS
- •REFERENCES
- •KEY FEATURES
- •CALCINEURIN INHIBITORS
- •CICLOSPORIN (CYCLOSPORIN: CsA)
- •Key features, introduction, and history
- •Pharmacology
- •Drug effects in human nonocular diseases
- •Drug use in retinal diseases
- •Pediatric case series
- •EFFICACY AND COMPARISON WITH OTHER AGENTS
- •Ciclosporin versus tacrolimus
- •TACROLIMUS
- •Key features, introduction, and history
- •Pharmacology
- •Drug effects in human nonocular diseases
- •Drug use in retinal diseases
- •Summary and key points
- •ANTIMETABOLITES
- •MYCOPHENOLATE MOFETIL (MMF)
- •Key features, introduction, and history
- •Pharmacology
- •Drug mechanism
- •Drug effects in human nonocular diseases
- •Drug use in retinal diseases
- •Pediatric case series
- •METHOTREXATE
- •Key features, introduction, and history
- •Pharmacology
- •Drug mechanism
- •Drug effects in human nonocular diseases
- •Drug use in retinal diseases
- •Pediatric case series
- •Intravitreal methotrexate injection
- •AZATHIOPRINE
- •Key features, introduction, and history
- •Pharmacology
- •Drug mechanism
- •Drug effects in human nonocular diseases
- •Drug use in retinal diseases
- •Pediatric case series
- •Summary and key points
- •ALKYLATING AGENTS
- •CYCLOPHOSPHAMIDE
- •Key features, introduction, and history
- •Pharmacology
- •Drug effects in human nonocular diseases
- •Drug use in retinal diseases
- •Efficacy and comparison with other agents
- •CHLORAMBUCIL
- •Key features, introduction, and history
- •Pharmacology
- •Drug effects in human nonocular diseases
- •Drug use in retinal diseases
- •Efficacy and comparison with other agents
- •Summary and key points
- •SUMMARY
- •REFERENCES
- •KEY FEATURES
- •INTRODUCTION AND HISTORY
- •PHARMACOLOGY
- •DRUG MECHANISM
- •DRUG EFFECTS IN PRECLINICAL MODELS
- •SYSTEMIC AND OCULAR COMPLICATIONS AND TOXICITY
- •BIOACTIVITY IN HUMAN EYE DISEASES
- •NEOVASCULAR AMD PHASE I
- •NEOVASCULAR AMD PHASE III PROGRAM
- •SUMMARY AND KEY POINTS
- •REFERENCES
- •KEY FEATURES
- •INTRODUCTION AND HISTORY
- •PHARMACOLOGY
- •PHARMACOKINETICS
- •DRUG MECHANISM
- •DRUG USE IN RETINAL DISEASES
- •DIABETIC RETINOPATHY
- •RETINAL VEIN OCCLUSION
- •OTHERS
- •CONTRAINDICATIONS
- •OCULAR COMPLICATIONS AND TOXICITY
- •DRUG INTERACTIONS
- •SUMMARY AND KEY POINTS
- •REFERENCES
- •KEY FEATURES
- •INTRODUCTION TO PROTEIN KINASE C
- •PROTEIN KINASE C FAMILY
- •EFFECTS OF ACTIVATED PKC
- •PHARMACOLOGY OF RUBOXISTAURIN
- •EFFECT OF RUBOXISTAURIN IN HUMAN NONOCULAR DISEASES
- •Use of PKC Inhibitors in the treatment of diabetic macular edema and diabetic retinopathy
- •EFFICACY OF RUBOXISTAURIN IN THE TREATMENT OF DIABETIC RETINOPATHY
- •OCULAR AND SYSTEMIC COMPLICATIONS AND TOXICITY OF RUBOXISTAURIN
- •INTERACTION OF RUBOXISTAURIN WITH OTHER DRUGS
- •SUMMARY AND KEY POINTS
- •REFERENCES
- •KEY FEATURES
- •INTRODUCTION AND HISTORY OF SIRNA FOR RETINAL DISEASES
- •PHARMACOLOGY, DRUG MECHANISM, AND DRUG EFFECTS IN NONOCULAR DISEASES
- •DRUG USES IN RETINAL DISEASES
- •BEVASIRANIB FOR SUBFOVEAL CHOROIDAL NEOVASCULARIZATION
- •BEVASIRANIB FOR NEOVASCULAR MACULAR DEGENERATION: RESULTS
- •BEVASIRANIB FOR THE TREATMENT OF DIABETIC MACULAR EDEMA (DME)
- •SIRNA-027 FOR SUBFOVEAL CHOROIDAL NEOVASCULARIZATION
- •REDD14 NP
- •SUMMARY AND KEY POINTS
- •ACKNOWLEDGMENT
- •REFERENCES
- •Ocular gene therapy
- •KEY FEATURES
- •INTRODUCTION TO GENE THERAPY
- •CURRENT VIRAL VECTORS
- •VIRAL VECTOR-ASSOCIATED RISKS
- •VIRAL VERSUS NONVIRAL VECTORS
- •STRATEGIES FOR RECESSIVE VERSUS DOMINANT DISEASE
- •STRATEGIES FOR PROLIFERATIVE AND NEOPLASTIC OCULAR DISEASE
- •RETINOBLASTOMA GENE THERAPY CLINICAL TRIAL
- •GENE THERAPY FOR LEBER’S CONGENITAL AMAUROSIS TRIAL
- •SUMMARY AND KEYPOINTS: THE FUTURE OF GENE THERAPY
- •REFERENCES
- •KEY FEATURES
- •INTRODUCTION
- •MECHANISM OF PROTECTION: APPROACHES AND CHALLENGES
- •ANTIOXIDATIVE THERAPY
- •EXCITOTOXICITY
- •NEUROTROPHIC FACTORS
- •ANTIAPOPTOPIC THERAPY
- •SUMMARY AND KEY POINTS
- •REFERENCES
- •KEY FEATURES
- •INTRODUCTION AND HISTORY
- •PHARMACOLOGY
- •DRUG MECHANISM
- •PDT IN ONCOLOGICAL DISORDERS
- •PDT IN IMMUNE (NONONCOLOGICAL) DISORDERS
- •DRUG USE IN RETINAL DISEASES
- •AGE-RELATED MACULAR DEGENERATION
- •PATHOLOGIC MYOPIA
- •OTHER SUBFOVEAL AND JUXTAFOVEAL POSTINFLAMMATORY OR IDIOPATHIC CHOROIDAL NEOVASCULARIZATION
- •POLYPOIDAL CHOROIDAL VASCULOPATHY
- •CENTRAL SEROUS CHORIORETINOPATHY
- •INTRAOCULAR VASOPROLIFERATIVE TUMORS
- •RETINAL ASTROCYTOMA
- •CHOROIDAL OSTEOMA
- •CHOROIDAL MELANOMA
- •RETINOBLASTOMA
- •CONJUNCTIVAL IN SITU SQUAMOUS CELL CARCINOMA
- •EFFICACY AND COMPARISON WITH OTHER AGENTS
- •CONTRAINDICATIONS
- •OCULAR COMPLICATIONS AND TOXICITY
- •DRUG INTERACTIONS
- •SUMMARY AND KEY POINTS
- •REFERENCES
- •KEY FEATURES
- •INTRODUCTION
- •RETINOBLASTOMA (Tables 44.1 and 44.2)
- •GENERAL CONSIDERATIONS
- •CHEMOREDUCTION
- •AGENTS
- •RESULTS
- •CHEMOREDUCTION FAILURE
- •SIDE-EFFECTS
- •CHEMOTHERMOTHERAPY
- •PERIOCULAR AND SUBCONJUNCTIVAL CHEMOTHERAPY
- •INTRAVITREAL CHEMOTHERAPY
- •INTRA-ARTERIAL CHEMOTHERAPY
- •ADJUVANT CHEMOTHERAPY
- •NO CHOROIDAL, SCLERAL, OR POSTLAMINAR OPTIC NERVE INVOLVEMENT
- •CHOROIDAL INVASION
- •POSTLAMINAR OPTIC NERVE INVASION
- •TUMOR AT CUT OPTIC NERVE MARGIN
- •METASTATIC RETINOBLASTOMA
- •UVEAL METASTASIS
- •GENERAL CONSIDERATIONS
- •CHEMOTHERAPY
- •PROGNOSIS
- •UVEAL MELANOMA
- •METASTATIC UVEAL MELANOMA
- •INTRAOCULAR LYMPHOMA
- •GENERAL CONSIDERATIONS
- •TREATMENT
- •SUMMARY AND KEYPOINTS
- •REFERENCES
- •Antibiotics
- •INTRODUCTION
- •POTENTIAL NEW TREATMENT REGIMENS
- •TOPICAL FLUOROQUINOLONES
- •ORAL AND INTRAVENOUS ANTIBIOTICS
- •NASALLY APPLIED ANTIBIOTICS
- •ORAL, TOPICAL, AND INTRAVITREAL ANTIFUNGAL AGENTS
- •CONCLUSION
- •REFERENCES
- •SECTION 5: Pharmacotherapy and Surgery
- •KEY FEATURES (PHARMACOLOGY)
- •INTRODUCTION AND HISTORY
- •RHEOPHERESIS IN RETINAL DISEASES
- •AGE-RELATED MACULAR DEGENERATION
- •MAC-1 trial
- •Multicenter investigation of rheopheresis for AMD (MIRA-1)
- •DIABETIC MACULOPATHY
- •CENTRAL RETINAL VEIN OCCLUSION
- •UVEAL EFFUSION SYNDROME
- •Complications
- •SUMMARY
- •REFERENCES
- •Enzymatic vitrectomy and pharmacologic vitreodynamics
- •INTRODUCTION AND HISTORY
- •PHARMACOLOGY AND BIOCHEMISTRY
- •INDICATIONS
- •SURGICAL ADJUNCT
- •NONSURGICAL INDICATIONS
- •OPERATIVE TECHNIQUES
- •OUTCOMES
- •SUMMARY
- •REFERENCES
- •KEY FEATURES, INTRODUCTION, AND HISTORY
- •RATIONALE
- •PHARMACOLOGY AND BIOCHEMISTRY
- •INDICATIONS, OUTCOMES, AND COMPLICATIONS – VITAL DYES IN CHROMOVITRECTOMY
- •INDOCYANINE GREEN
- •INFRACYANINE GREEN
- •TRYPAN BLUE
- •PATENT BLUE
- •BRILLIANT BLUE
- •SODIUM FLUORESCEIN (SF)
- •TRIAMCINOLONE ACETONIDE
- •DYE INJECTION
- •MACULAR HOLE PROTECTION
- •SUMMARY AND KEY POINTS
- •REFERENCES
- •KEY FEATURES
- •INTRODUCTION AND HISTORY
- •BIOLOGICAL EFFECTS
- •INDICATIONS
- •CHOROIDAL MELANOMA
- •OTHER OCULAR TUMORS
- •OPERATIVE TECHNIQUES
- •PLAQUE PLACEMENT TECHNIQUE
- •EPIMACULAR BRACHYTHERAPY FOR AGE-RELATED MACULAR DEGENERATION
- •SURGICAL TECHNIQUE
- •OUTCOMES
- •CHOROIDAL MELANOMA
- •BRACHYTHERAPY FOR AGE-RELATED MACULAR DEGENERATION
- •COMPLICATIONS
- •RADIATION RETINOPATHY
- •OPTIC NEUROPATHY
- •LENS TOXICITY
- •SCLERA/CHOROID TOXICITY
- •SUMMARY AND KEY POINTS
- •REFERENCES
- •INTRODUCTION
- •RPE DISEASE AND INDICATIONS FOR TREATMENT BY TRANSPLANTATION
- •BRUCH’S MEMBRANE AS A SUBSTRATE FOR TRANSPLANTED RPE
- •HISTORICAL DEVELOPMENT OF RPE TREATMENT
- •AUTOLOGOUS TREATMENT
- •IRIS PIGMENT EPITHELIUM
- •RETINAL PIGMENT EPITHELIUM
- •Suspension
- •RPE-BM Choroid Sheet
- •TISSUE ENGINEERING AND RPE REPLACEMENT STRATEGIES
- •PROSTHESIS OR TISSUE ENGINEERING OF BRUCH’S MEMBRANE
- •STEM CELLS
- •Embryonic stem cells
- •Bone marrow-derived cells
- •MANAGING DECONSTRUCTIVE REACTIONS INDUCED BY RETINAL DETACHMENT
- •CONCLUSIONS AND FUTURE DIRECTIONS
- •ACKNOWLEDGMENTS
- •REFERENCES
- •SECTION 6: The Last Words
- •Off-label drugs and the impact of the Food and Drug Administration in the treatment of retinal disease
- •INTRODUCTION
- •OFF-LABEL DRUG USAGE AND THE FOOD AND DRUG ADMINISTRATION
- •HISTORICAL PERSPECTIVES
- •FDA APPROVAL PROCESS
- •THE CONCEPT OF “OFF-LABEL”
- •“INVESTIGATIONAL USAGE OF DRUGS”
- •COMPOUNDING PHARMACIES
- •RISK MANAGEMENT ISSUES
- •INFORMED CONSENT
- •MEDICAL PAYMENT/COVERAGE
- •NATIONAL COVERAGE DETERMINATION
- •CLINICAL TRIALS
- •SUMMARY AND KEY POINTS
- •REFERENCES
- •INTRODUCTION
- •HISTORY
- •KEY CONCEPTS
- •EVIDENCE-BASED MEDICINE
- •TYPES OF PHARMACOECONOMIC ANALYSIS
- •COST MINIMIZATION ANALYSIS
- •COST–BENEFIT ANALYSIS
- •COST-EFFECTIVENESS ANALYSIS
- •Cost-effectiveness analysis
- •COST–UTILITY ANALYSIS
- •Quality of life: Function-based instruments
- •Quality of life: Preference-based instruments
- •Utility gain
- •Value gain
- •Value trumps cost
- •Cost–utility ratio
- •Cost-effectiveness standards
- •Discounting5
- •Value-based medicine
- •Standardization
- •Patient respondents
- •COST PERSPECTIVE
- •SUMMARY AND KEY POINTS
- •REFERENCES
- •Future perspectives:
- •INTRODUCTION
- •KEY FEATURES
- •ANGIOGENESIS AND NEOVASCULAR AGE-RELATED MACULAR DEGENERATION
- •TYROSINE KINASE INHIBITORS
- •PDGF INHIBITORS
- •INTEGRIN INHIBITORS
- •SMALL INTERFERING RNA
- •BIOACTIVE LIPIDS
- •NONNEOVASCULAR AGE-RELATED MACULAR DEGENERATION
- •COMPLEMENT INHIBITORS
- •DIABETIC MACULAR EDEMA
- •INHIBITION OF INFLAMMATION
- •SUMMARY AND KEY POINTS
- •ACKNOWLEDGMENT
- •REFERENCES
- •Index
Transplantation Epithelial Pigment Retinal Human of Status• 50chapteCurrent
inner cell mass), yet recent developments in the field may show promise in this route.
Bone marrow-derived cells
Bone marrow-derived stromal cells have recently been shown to differentiate into a wide variety of tissues and were also demonstrated to participate in the regeneration of many acutely injured tissues in the adult. Many groups have now shown recruitment of bone marrowderived cells into subretinal space in CNV or sodium iodate mice models, with the acquisition of RPE-like properties.32,33
Uncommitted hematopoietic stem cells and so-called facilitating cells have previously been more specifically implicated in the phenomenon. Coculture of green fluorescent protein-labeled, Sca+ bone marrow cells with mitomycin C-treated RPE leads to acquisition of RPE-specific proteins of the former.34 An enriched CD133+ fraction of hematopoietic progenitor cells injected intravitreally in albino mice adopted RPE characteristics such as pigmentation or expression of RPE-specific proteins in the subretinal space.35 Further elucidation of the mechanisms leading to these promising observations is important, since this would eventually provide a good source for autologous cells in elderly patients.
MANAGING DECONSTRUCTIVE REACTIONS INDUCED BY RETINAL DETACHMENT
RPE transplantation requires manipulation in the subretinal space and thus unavoidably creates temporary retinal detachments (RD). It is therefore important to discuss the consequences of this maneuver.
Work over the past two decades has elucidated many remodeling changes occurring with separation of both retinal layers; these changes are described in depth in a splendid review by Fisher et al.36 Virtually all cell types of the retina, including the RPE, have been shown to participate in “deconstructive” processing upon detachment. Müller and photoreceptor reactions have been studied most widely. Alterations in both cell populations are early avenues to retinal gliosis, which in turn causes synaptic “rewiring.”37 This phenomenon may explain why anatomically reattached patients often require many months until normal vision returns.
Although candidates for RPE transplantation will already have a retinal pathology and the dimension of surgical trauma might be small or negligible, retinal detachment-related phenomena may need consideration.
Given that macular translocation surgery creates panretinal detachments and some patients are able to recover up to 20/30 vision, this suggests that clinically the retina is able to tolerate such interventions. In analogy to the latter technique, the retina can be relatively atraumatically detached with a Ca and Mg-free solution. Reattachment is expected to be relatively rapid, as was shown in the rabbit. Neuroprotective strategies during detachment and reattachment, as recently proposed by Kubay et al.,38 will also be a future key to success for RPE replacement strategies.
CONCLUSIONS AND FUTURE DIRECTIONS
Cellular replacement strategies for the RPE have the potential of being a curative therapy for all AMD forms and related retinal degenerations, yet clinical protocols show only modest success to the present date. Research over more than two decades in this and related fields has elucidated many potential mechanisms, in addition to challenges and drawbacks. Encouraging early RPE transplantation experiments under controlled laboratory settings were soon challenged by a variety of factors in patients with AMD. The unconditional eventual rejection and/or lack functional recovery with homologous transplants had set the stage for autologous transplants. Here then, many mechanisms came into play, aging and AMD-related alterations of the RPE and
BM perhaps being the foremost. Nevertheless, transplantation of uncultured autologous RPE in patients with neovascular AMD has demonstrated some success. Firstly, there is evidence that suggests improved visual rehabilitation along with a low complication rate after RPE suspension transplantation, when compared to membrane removal alone. Further, the transplantation of a full-thickness patch of RPE and choroid for the first time demonstrates long-term survival of transplanted RPE cells in the subretinal space of patients with neovascular AMD. However, the technically challenging surgery and high complication rate ethically question this treatment modality at present.
The shortcomings of freshly harvested RPE for transplantation could be overcome with tissue engineering to deliver RPE on a BM prosthesis. Stem cell-derived RPE-like cells were generated from several stem cell sources. They represent promising new sources for RPE replacement. However, in analogy, somatic RPE transplantation, cellular delivery, and aging changes in BM need to be addressed with prosthetics to ensure long-term function of stem cell-derived RPE. The need for an effective cell-based therapy is undisputable, since patients will always present at different stages of disease progression. Whether RPE transplantation ultimately represents a curative solution is unclear, but its potential application to all forms of AMD and related entities make it a worthwhile therapeutic endeavor.
ACKNOWLEDGMENTS
The authors would like to thank Jean-Marie Parel and Wiliam Lee from the Ophthalmic Biophysics Center at the Bascom Palmer Eye Institute for developing cannulas for RPE suspension transplantation. Dr. Stanzel is grateful for support received via an E. Schrödinger postdoctoral fellowship (J2463-B13) from the Austrian Science Foundation (FWF), and Adele Rabensteiner Awards in 2002, 2005, and 2006 from the Austrian Ophthalmic Society and Rüdiger Foundation, Germany in 2009.
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Surgery and Pharmacotherapy • 5 section
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