- •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
|
0 |
Change in retinal thickness |
|
|
|
−50 |
|
|
|
in microns |
−100 |
|
|
|
−150 |
|
|
|
|
Reductions |
−200 |
|
|
|
−250 |
|
|
|
|
|
|
|
|
|
|
−300 |
|
|
|
|
−350 |
|
|
|
|
0 |
4 |
8 |
12 |
A |
|
|
Study week |
|
|
|
|
|
|
0.5 mg 4 wk |
|
2.0 mg 12 wk |
|
4.0 mg 12 wk |
|
|
|||
0.5 mg 12 wk |
|
2.0 mg 4 wk |
|
|
|
|
|
|
15 |
Change in best corrected visual acuity |
|
|
|
|
|
||
gained |
10 |
|
|
q4 |
|
|
|
weekly |
|
|
|
|
dosing |
|
Letters |
|
|
|
|
5 |
|
|
q12 |
|
|
|
|
||
|
|
|
|
|
|
|
|
|
weekly |
|
|
|
|
dosing |
|
0 |
|
|
|
B |
0 |
4 |
8 |
12 |
|
|
Study week |
|
|
0.5 mg 4 wk |
|
2.0 mg 4 wk |
|
4.0 mg 12 wk |
|
|
|
||||
0.5 mg 12 wk |
|
|
2.0 mg 12 wk |
|
|
|
|
|
|
||
weeks, but no less frequently than every 12 weeks, based on specific retreatment criteria.16
The primary objective will be to assess the efficacy of intravitreally administered VEGF Trap-Eye compared to ranibizumab in a noninferiority paradigm in preventing moderate vision loss in subjects with all subtypes of neovascular AMD. One secondary objective will be to assess the safety and tolerability of repeated intravitreal administration of VEGF Trap-Eye in patients with all subtypes of neovascular AMD for periods up to 2 years. Another secondary objective will be to assess the effect of repeated intravitreal administrations of VEGF Trap-Eye on vision-related quality of life (QOL) in subjects with all subtypes of neovascular AMD, as assessed using the National Eye Institute VFQ-25 questionnaire.16
DIABETIC MACULAR EDEMA PHASe I
CLINICaL STUDY
The initial phase I study of VEGF Trap-Eye in DME, CLEAR-IT DME, was an exploratory study of the safety, tolerability, and biological effect of a single intravitreal administration of VEGF Trap-Eye in patients with DME.37 The study was conducted at two centers involving 5 patients. It was an open-label study evaluating a single intravitreal injection of 4 mg VEGF Trap-Eye. Patients were followed for 6 weeks for safety, BCVA, centerpoint thickness, and macular volume by OCT.
The maximum change from baseline in key outcome measures at 6 weeks included reductions in centerpoint retinal thickness, with a mean reduction of −115.4 µm and a median reduction of −118 µm (P < 0.03). Macular volume was reduced by a mean of −1 µm3 and a median of −0.6 µm3 (P < 0.04). ETDRS BCVA letters improved by a mean of 6.8 and a median of 9 (P < 0.03).37
Intravitreal injection of VEGF Trap-Eye for DME in a phase I study showed only mild ocular adverse events that were related to the injection procedure. No serious ocular adverse events were reported.37
A phase II dose-ranging study comparing various doses of VEGF Trap-Eye administered at various dosing intervals to focal laser treatment is currently in development.
Figure 37.5 Retinal thickness and visual acuity in individual groups are shown separately (mean ± sem). Monthly and quarterly dosing did not result in substantially different results at 8 weeks. Even quarterly dosing resulted in substantial improvements at week 8 (range of means, 4.4–5.4 letters gained), and at week 12 (range of means, 2.8–5.1 letters gained). Monthly dosing was numerically superior at 12 weeks, though not statistically significant. Monthly dosing resulted in continued best corrected visual acuity (BCVA) improvement through week 12 (range of means at week 12, 8.8–10.4 letters gained).
administration versus monthly dosing of ranibizumab in patients with neovascular AMD. Four equal treatment groups will be followed for a 52-week primary endpoint. Three VEGF Trap-Eye treatment groups, 0.5 mg q 4 weeks, 2.0 mg q 4 weeks, and 2.0 mg q 8 weeks, will be compared with ranibizumab 0.5 mg q 4 weeks. A 3-monthly loading dose of VEGF Trap-Eye will be administered to all VEGF Trap-Eye subgroups. All VEGF Trap-Eye and ranibizumab patients will be treated on a PRN basis in year 2, with reinjection required at least once every 3 months. Men and women 50 years of age or older with subfoveal CNV due to neovascular AMD will be included who meet the inclusion criteria of: (1) active primary subfoveal CNV lesions secondary to AMD (including juxtafoveal lesions that affect the fovea); (2) ≥50% active CNV; and (3) best corrected ETDRS protocol visual acuity of ≤20/40–20/320 (letter score of 73−25) in the study eye.
During the second year of study, patients will be evaluated every 4 weeks and will receive an intravitreal injection at least every 12 weeks. During this period, injections may be given as frequently as every 4
SUMMARY AND KEY POINTS
Existing anti-VEGF therapies have transformed the treatment of wet AMD into a disease in which improvement of vision may be expected by both patients and physicians. However, medications that allow for greater efficacy, or efficacy for more patients, and/or a longer dosing interval are still desired by physicians and patients, reflecting a continuing medical need for better treatments.
VEGF Trap-Eye, a fusion protein of VEGF receptors 1 and 2, is a promising treatment currently in development. It is fully human and has high affinity, binding VEGF more tightly than native receptors or monoclonal antibodies. It blocks all VEGF-A isoforms, VEGF-B, and PlGF, and, based on its molecular weight, should penetrate all retinal layers. Unlike antibody complexes, VEGF-Trap forms inert complexes that do not interact further with the VEGF receptor.
VEGF Trap-Eye has thus far demonstrated clinical activity with an acceptable safety profile in clinical trials. The CLEAR-IT DME study demonstrated reduced retinal thickness and improved vision in this common visual disease associated with diabetes. In CLEAR-IT 1 and 2 AMD studies, improved visual acuity and reduced retinal thickness were demonstrated. VEGF Trap-Eye was also generally safe and well tolerated. The two current phase III studies for neovascular AMD, VIEW 1 (USA and Canada) and VIEW 2 (Europe, Asia Pacific, Japan, and Latin America), will help to determine whether VEGF Trap-Eye can offer differential efficacy and/or longer dosing intervals relative to currently available agents.
It is hoped that future armamentaria for managing retinal vascular diseases will include VEGF Trap-Eye as one of their therapeutic agents.
Diseases Retinal in Mechanisms and Drugs • 4 section
263
• 37Trapchapter-VEGF Proteins: Fusion
REFERENCES
1.Economides AN, Carpenter LR, Rudge JS, et al. Cytokine traps: multicomponent, high-affinity blockers of cytokine action. Nat Med 2003;9:47–52.
2.Holash J, Davis S, Papadopoulos N, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci USA 2002;99:11393–11398.
3.Breen EC. VEGF in biological control. J Cell Biochem 2007;102:1358–1367.
4.Olsson AK, Dimberg A, Kreuger J, et al. VEGF receptor signalling − in control of vascular function. Nat Rev Mol Cell Biol 2006;7:359–371.
5.Rudge JS, Thurston G, Davis S, et al. VEGF trap as a novel antiangiogenic treatment currently in clinical trials for cancer and eye diseases, and VelociGenebased discovery of the next generation of angiogenesis targets. Cold Spring Harb Symp Quant Biol 2005;70:411–418.
6.Cursiefen C, Chen L, Borges LP, et al. VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. J Clin Invest 2004;113:1040–1050.
7.Otrock ZK, Makarem JA, Shamseddine AI. Vascular endothelial growth factor family of ligands and receptors: review. Blood Cells Mol Dis 2007;38:258–268.
8.Jain RK, Xu L. alphaPlGF: a new kid on the antiangiogenesis block. Cell 2007;131:443–445.
9.Odorisio T, Cianfarani F, Failla CM, et al. The placenta growth factor in skin angiogenesis. J Dermatol Sci 2006;41:11–19.
10.Carmeliet P, Moons L, Luttun A, et al. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med 2001;7:575–583.
11.Ziche M, Maglione D, Ribatti D, et al. Placenta growth factor-1 is chemotactic, mitogenic, and angiogenic. Lab Invest 1997;76:517–531.
12.Rakic JM, Lambert V, Devy L, et al. Placental growth factor, a member of the VEGF family, contributes to the development of choroidal neovascularization. Invest Ophthalmol Vis Sci 2003;44:3186–3193.
13.Khaliq A, Foreman D, Ahmed A, et al. Increased expression of placenta growth factor in proliferative diabetic retinopathy. Lab Invest 1998;78:109–116.
14.Mitamura Y, Tashimo A, Ohtsuka K, et al. Placenta growth factor and vascular endothelial growth factor in the vitreous of patients with proliferative vitreoretinopathy. Clin Experiment Ophthalmol 2005;33: 226–227.
15.Chappelow AV, Kaiser PK. Neovascular age-related macular degeneration: potential therapies. Drugs 2008;68:1029–1036.
16.Regeneron. 2008. Data on file.
17.Lowe J, Araujo J, Yang J, et al. Ranibizumab inhibits multiple forms of biologically active vascular endothelial growth factor in vitro and in vivo. Exp Eye Res 2007;85:425–430.
18.Ferrara N, Chen H, Davis-Smyth T, et al. Vascular endothelial growth factor is essential for corpus luteum angiogenesis. Nat Med 1998;4:
336–340.
19.Gerber HP, Hillan KJ, Ryan AM, et al. VEGF is required for growth and survival in neonatal mice. Development 1999a;126:1149–1159.
20.Gerber HP, Vu TH, Ryan AM, et al. VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat Med 1999b;5:623–628.
21.Goldman CK, Kendall RL, Cabrera G, et al. Paracrine expression of a native soluble vascular endothelial growth factor receptor inhibits tumor growth, metastasis, and mortality rate. Proc Natl Acad Sci USA 1998;95: 8795–8800.
22.Millauer B, Longhi MP, Plate KH, et al. Dominant-negative inhibition of Flk-1 suppresses the growth of many tumor types in vivo. Cancer Res 1996;56:1615–1620.
23.Kaiser PK. Antivascular endothelial growth factor agents and their development: therapeutic implications in ocular diseases. Am J Ophthalmol 2006;142:660–668.
24.Konner J, Dupont J. Use of soluble recombinant decoy receptor vascular endothelial growth factor trap (VEGF Trap) to inhibit vascular endothelial growth factor activity. Clin Colorectal Cancer 2004;4(Suppl. 2):S81–S85.
25.Furfine E, Coppi A, Koehler-Stec EM, et al. Pharmacokinetics and ocular tissue penetration of VEGF Trap after intravitreal injections in rabbits. Annual Meeting of The Association for Research in Vision and Ophthalmology (ARVO); 2006 April 30-May 4; Fort Lauderdale, FL.
26.Pieramici DJ, Rabena MD. Anti-VEGF therapy: comparison of current and future agents. Eye 2008;22:1330–1336.
27.Cao J, Song H, Renard RA, et al. Systemic or intravitreal administration of VEGF Trap suppresses vascular leak and leukostasis in the retinas of diabetic rats. Invest Ophthalmol Vis Sci 2006;47:e-abstract 1745.
28.Stewart MW, Rosenfeld PJ. Predicted biological activity of intravitreal VEGF Trap. Br J Ophthalmol 2008;92:667–668.
29.Stewart MW. Predicted biologic activity of intravitreal bevacizumab. Retina 2007;27:1196–1200.
30.Rudge JS, Holash J, Hylton D, et al. Inaugural article: VEGF Trap complex formation measures production rates of VEGF, providing a biomarker for predicting efficacious angiogenic blockade. Proc Natl Acad Sci USA 2007;104:18363–18370.
31.Saishin Y, Saishin Y, Takahashi K, et al. VEGF-TRAP(R1R2) suppresses choroidal neovascularization and VEGF-induced breakdown of the blood–retinal barrier. J Cell Physiol 2003;195:241–248.
32.Wiegand SJ, Zimmer E, Nork TM, et al. VEGF Trap both prevents experimental choroidal neovascularization and causes regression of established lesions in non-human primates. Invest Ophthalmol Vis Sci 2005;46:e-abstract 1411.
33.Zimmer E, Christian BJ, Miller PE. Safety evaluation of intravitreal administration of VEGF Trap in cynomolgus monkeys for 13 weeks. Annual Meeting of The Association for Research in Vision and Ophthalmology (ARVO); 2006 April 30-May 4; Fort Lauderdale.
34.Nguyen QD, Hariprasad S, Browning DJ, et al. Interim results from a phase 1, safety, tolerability, and bioactivity study of intravitreal VEGF trap in patients with neovascular age-related macular degeneration: the CLEAR-IT 1 study. Annual Meeting of The Association for Research in Vision and Ophthalmology (ARVO); 2007 May 6–10; Fort Lauderdale.
35.Nguyen QD, Shah SM, Browning DJ, et al. Results of a phase I, doseescalation, safety, tolerability, and bioactivity study of intravitreous VEGF Trap in patients with neovascular age-related macular degeneration. Annual Meeting of The Association for Research in Vision and Ophthalmology (ARVO); 2006 April 30-May 4; Fort Lauderdale.
36.Benz MS, Nguyen QD, Chu K, et al. Interim results of the Phase II, randomized, controlled doseand interval-ranging study of repeated intravitreal VEGF trap administration in patients with neovascular age-related macular degeneration (AMD). Annual Meeting of The Association for Research in Vision and Ophthalmology (ARVO); 2007 May 6–10; Fort Lauderdale.
37.Do DV, Nguyen QD, Shah SM, et al. An exploratory study of the safety, tolerability and bioactivity of a single intravitreal injection of vascular endothelial growth factor Trap-Eye in patients with diabetic macular oedema. Br J Ophthalmol 2009 Feb;93(2):144–149.
264