- •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
A B
Figure 47.2 Results of Microplasmin for Vitrectomy IIT (MIVI-IIT) study. (A) Optical coherence tomography (OCT) demonstrating vitreomacular traction with visual acuity (VA) of 20/100. (B) OCT image 3 months after microplasmin intravitreal injection. There is resolution of the vitreous traction and VA has improved to 20/16.
Recent studies suggest that a pharmacologic PVD may alter the flow of molecules across the vitreoretinal interface. A microplasmin-induced PVD in animals has been shown to increase vitreal oxygen levels and increase the rate of oxygen exchange within the vitreous cavity.20 This effect is not seen with hyaluronidase and liquefaction of the vitreous cavity alone.20 This observation suggests that an attached posterior hyaloid may present a semipermeable barrier at the vitreoretinal junction. The change in oxygen molecular flux may be seen as a marker for the behavior of other molecules in the extracellular matrix of the vitreous cavity, particularly the vitreous cortex. In fact, preliminary data from cat models suggest a microplasmin-induced PVD leads to decreased levels of vitreal vascular endothelial growth factor,39 which is an important factor in the pathogenesis of diabetic macular edema and neovascularization.40,41 It is possible that an age-related PVD or a pharmacologic-induced PVD may alter the flux of molecules in the vitreous cavity and influence the concentration of other vitreal growth factors. Prospective clinical trials will be needed to address this theory.
OPERATIVE TECHNIQUES
The ability to induce a complete PVD in 30 minutes with plasmin or microplasmin is significant. This seems to be an acceptable amount of delayforpharmacologicvitreolysistohaveaclinicaleffect.Microplasmin could feasibly be injected in the operating room or in the clinic prior to surgery. In the operating room, this injection would not cause an insurmountable delay prior to beginning a vitrectomy; in the clinic setting, it would be reasonable for a patient to wait 30 minutes or longer for a possible repeat examination in order to ensure the agent’s efficacy and to identify potential complications. Both plasmin and microplasmin are clear solutions that do not alter surgical planning or techniques.
prematurity,44 congenital X-linked retinoschisis,45 and other pediatric vitreoretinopathies.43
Plasmin enzyme has also shown promising results with adult vitreoretinal disorders. APE-assisted vitrectomy for stage 3 macular holes allows for easier removal of the posterior hyaloid, increased spontaneous PVD, and reduced operative time.3 APE-assisted vitrectomy may also improve removal of the posterior hyaloid,5,42 reduce surgical time,42 and reduce iatrogenic retinal tears42 in patients with diabetic tractional retinal detachments. Furthermore, patients with diabetic macular edema have shown improved visual acuity after APE-assisted vitrectomy but with mixed results regarding the resolution of edema.5,28
COMPLICATIONS AND HOW TO
AVOID THEM
A retinal tear is an intrinsic risk during PVD creation, especially in patients with abnormal vitreoretinal adhesions, such as lattice degeneration. Thus, enzymatic vitrectomy presents the inherent risk of causing a retinal tear and subsequent retinal detachment. Although a retinal tear has not been reported as a result of pharmacologic manipulation of the vitreous, closely monitoring patients following microplasmin injection would be prudent in order to identify retinal tears early. Prophylactic laser retinopexy around suspicious lesions prior to enzyme injection may be advisable.
Intravitreal injections also present the inherent risk of infection. The incidence of endophthalmitis after enzymatic vitrectomy has not been reported; however, it is very rare (0.029%) in patients receiving intravitreal injections for other indications.46 Prophylactic antiseptic solutions, sterile technique, and topical antibiotics are appropriate for the prevention of such infections.
OUTCOMES |
SUMMARY |
|
|
|
|
Plasmin and microplasmin are the most widely used agents for enzymatic vitrectomy. Multiple small case series have reported favorable results with APE as a surgical adjunct,3–5,28,42–45 and clinical trials are currently under way with microplasmin.
APE and microplasmin may be most beneficial as a surgical adjunct in pediatric cases, whereby the vitreous is especially adherent to the retina and poses an increased risk of complications with mechanical separation. APE-assisted vitrectomy allows for easier peeling of the vitreous gel with a reduced risk of causing iatrogenic retinal breaks in cases of pediatric traumatic macular holes,4 stage 5 retinopathy of
The emerging field of pharmacologic vitreodynamics presents a new frontier in vitreoretinal surgery. The ability to induce vitreous liquefaction and a complete PVD with a single intravitreal injection has potential implications for the management of multiple vitreoretinopathies. Enzymatic vitrectomy may help to reduce vitreous viscosity, thereby facilitating removal during vitrectomy and reducing surgical time, especially when using smaller-gauge vitrectomy instruments. The induction of a PVD also has the potential to reduce intraoperative complications. As we improve our understanding of the molecular flux in the vitreous cavity, pharmacologic vitreodynamics will likely become
Surgery and Pharmacotherapy • 5 section
329
Vitreodynamics Pharmacologic• 47 chapterand Vitrectomy Enzymatic
more important as it may allow for improved manipulation of intravitreal molecules.
Key points
•Pharmacologic agents have been developed to create vitreous liquefaction and a PVD.
•Intravitreal surgical adjuncts may facilitate vitreous removal and reduce intraoperative complications.
•APE can successfully cause vitreous liquefaction and induce a PVD.
•Microplasmin is a recombinant protein that can create a PVD in animal models. It is currently being investigated in clinical trials.
•A Food and Drug Administration phase III clinical trial is currently under way to determine if microplasmin can be used as a substitute for surgical intervention in patients with abnormal vitreoretinal adhesions.
REFERENCES
1.Sebag J. Pharmacologic vitreolysis. Retina 1998;18(1):1–3.
2.Gandorfer A, Rohleder M, Sethi C, et al. Posterior vitreous detachment induced by microplasmin. Invest Ophthalmol Vis Sci 2004;45(2): 641–647.
3.Trese MT, Williams GA, Hartzer MK. A new approach to stage 3 macular holes. Ophthalmol 2000;107(8):1607–1611.
4.Margherio AR, Margherio RR, Hartzer M, et al. Plasmin enzyme-assisted vitrectomy in traumatic pediatric macular holes. Ophthalmol 1998;105(9): 1617–1620.
5.Williams JG, Trese MT, Williams GS, et al. Autologous plasmin enzyme in the surgical management of diabetic retinopathy. Ophthalmol 2001; 108(10):1902–1905.
6.Verstraeten TC, Chapman C, Hartzer M, et al. Pharmacologic induction of posterior vitreous detachment in the rabbit. Arch Ophthalmol 1993;111(6): 849–854.
7.Asami T, Terasaki H, Kachi S, et al. Ultrastructure of internal limiting membrane removed during plasmin-assisted vitrectomy from eyes with diabetic macular edema. Ophthalmol 2004;111(2):231–237.
8.Sebag J, Ansari RR, Suh KI. Pharmacologic vitreolysis with microplasminin increases vitreous diffusion coefficients. Graefe’s Arch Clin Exp Ophthalmol 2007;245(4):576–580.
9.Sebag J. Molecular biology of pharmacologic vitreolysis. Trans Am Ophthalmol Soc 2005;103:473–494.
10.Gass JD. Macular dysfunction caused by vitreous and vitreoretinal interface abnormalities. In: Gass JD, editor. Stereoscopic atlas of macular diseases: Diagnosis and treatment (Volume 2). St. Louis: Mosby, Inc.; 1997.
p. 903–973.
11.Kohno T, Sorgente N, Ishibashi T, et al. Immunofluorescent studies of fibronectin and laminin in the human eye. Invest Ophthalmol Vis Sci 1987;28(3):506–514.
12.Trese MT. Enzymatic-assisted vitrectomy. Eye 2002;16(4):365–368.
13.Hageman GS, Russell SR. Chondroitinate-mediated disinsertion of the primate vitreous body. Invest Ophthalmol Vis Sci 1994;35(suppl):28.
14.Hermel M, Schrage NF. Efficacy of plasmin enzymes and chondroitinase ABC in creating posterior vitreous separation in the pig: a masked, placebo-controlled in vivo study. Grafes Arch Clin Exp Ophthalmol 2007;245(3):399–406.
15.Zhu D, Chen H, Xu X. Effects of intravitreal dispase on vitreoretinal interface in rabbits. Curr Eye Res 2006;31(11):935–946.
16.Wang F, Wang Z, Sun X, et al. Safety and efficacy of dispase and plasmin in pharmacologic vitreolysis. Invest Ophthalmol Vis Sci 2004;45(9): 3286–3290.
17.Jorge R, Oyamaguchi EK, Cardillo JA, et al. Intravitreal injection of dispase causes retinal hemorrhages in rabbit and human eyes. Curr Eye Res 2003;26(2):107–112.
18.Kuppermann BD, Thomas EL, De Smet MD, et al. Safety results of two phase III trials of an intravitreous injection of highly purified ovine hyaluronidase (Vitrase®) for the management of vitreous hemorrhage. Am J Ophthalmol 2005;140(4):585–597.
19.Kuppermann BD, Thomas EL, De Smet MD, et al. Pooled efficacy results from two multinational randomized controlled clinical trials of a single
intravitreous injection of highly purified ovine hyaluronidase (Vitrase®) for the management of vitreous hemorrhage. Am J Ophthalmol 2005;140(4): 573–584.
20.Quiram PA, Leverenz VA, Baker RM, et al. Microplasm-induced posterior vitreous detachment affects vitreous oxygen levels. Retina 2007;27(8): 1090–1096.
21.Wang Z, Zhang X, Xu X, et al. PVD following plasmin but not hyaluronidase: Implications for combination pharmacologic vitreolysis therapy. Retina 2005;25(1):38–43.
22.Hikichi T, Kado M, Yoshida A. Intravitreal injection of hyaluronidase cannot induce posterior vitreous detachment in the rabbit. Retina 2000;20(2):195–198.
23.Liotta LA, Goldfarb RH, Brundage R, et al. Effect of plasminogen activator (urokinase), plasmin, and thrombin on glycoprotein and collagenous components of basement membrane. Cancer Res 1981;41(11 Pt 1): 4629–4636.
24.Uemura A, Nakamura M, Kachi S, et al. Effect of plasmin on laminin and fibronectin during plasmin-assisted vitrectomy. Arch Ophthalmol 2005;123(2):209–213.
25.Dano K, Andreasen PA, Grondahl-Hansen J, et al. Plasminogen activators, tissue degradation, and cancer. Adv Cancer Res 1985;44:139–266.
26.Takano A, Hirata A, Inomata Y, et al. Intravitreal plasmin injection activates endogenous matrix metalloproteinase-2 in rabbit and human vitreous. Am J Ophthalmol 2005;140(4):654–660.
27.Rizzo S, Pellegrini G, Benocci F, et al. Autologous plasmin for pharmacologic vitreolysis prepared 1 hour before surgery. Retina 2006;26(7):792–796.
28.Azzolini C, D’Angelo A, Maestranzi G, et al. Intrasurgical plasmin enzyme in diabetic macular edema. Am J Ophthalmol 2004;138(4):560–566.
29.Urano T, Ihara H, Umemura K, et al. The profibrinolytic enzyme subtilisin NAT purified from Bacillus subtilis cleaves and inactivates plasminogen activator inhibitor type I. J Biol Chem 2001;276(27):24690–24696.
30.Takano A, Hirata A, Ogasawara K, et al. Posterior vitreous detachment induced by nattokinase (subtilisin NAT): A novel enzyme for pharmacologic vitreolysis. Invest Ophthalmol Vis Sci 2006;47(5):2075–2079.
31.Nagai N, Demarsin E, Van Hoef B, et al. Recombinant human microplasmin: production and potential therapeutic properties. Thromb Haemost 2003;1(2):307–313.
32.Sakuma T, Tanaka M, Mitzota A, et al. Safety of in vivo pharmacologic vitreolysis with recombinant microplasmin in rabbit eyes. Invest Ophthalmol Vis Sci 2005;46(9):3295–3299.
33.Gandorfer A, Ulbig M, Kampik A. Plasmin-assisted vitrectomy eliminates cortical vitreous remnants. Eye 2002;16(1):95–97.
34.Sebag J. Diabetic vitreopathy. Ophthalmology 1996;103(2):205–206.
35.Schwartz SD, Alexander R, Hiscott P, et al. Recognition of vitreoschisis in proliferative diabetic retinopathy: A useful landmark in vitrectomy for diabetic traction retinal detachment. Ophthalmology 1996;103(2):323–328.
36.Russell SR, Hageman GS. Optic disc, foveal, and extrafoveal damage due to surgical separation of the vitreous. Arch Ophthalmol 2001;119(11):153– 1658.
37.Ono R, Kakehashi A, Yamagami H, et al. Prospective assessment of proliferative diabetic retinopathy with observations of posterior vitreous detachment. Int Ophthalmol 2005;26(1–2):15–19.
38.Krebs I, Brannath W, Glittenberg C, et al. Posterior vitreomacular adhesion: A potential risk factor for exudative age-related macular degeneration? Am J Ophthalmol 2007;144(5):741–746.
39.Quiram PA, Leverenz V, Baker R, et al. Enzymatic induction of a posterior vitreous detachment alters molecular vitreodynamics in animal models. Invest Ophthalmol Vis Sci 2007. Abstract no. 83.
40.Patel JI, Tombran-Tink J, Hykin PG, et al. Vitreous and aqueous concentrations of proangiogenic, antiangiogenic factors and other cytokines in diabetic retinopathy patients with macular edema: implications for structural differences in macular profiles. Exp Eye Res 2006;82(5):798–806.
41.Boulton M, Gregor Z, McLeod D, et al. Intravitreal growth factors in proliferative diabetic retinopathy: correlation with neovascular activity and glycaemic management. Br J Ophthalmol 1997;81(3):228–233.
42.Hirata A, Takano A, Inomata Y, et al. Plasmin-assisted vitrectomy for management of proliferative membrane in proliferative diabetic retinopathy: A pilot study. Retina 2007;27(8):1074–1078.
43.Joshi MM, Ciaccia S, Trese MT, et al. Posterior hyaloid contracture in pediatric vitreoretinopathies. Retina 2006;26(7):S38–S41.
44.Tsukahara Y, Honda S. Autologous plasmin-assisted vitrectomy for stage 5 retinopathy of prematurity: A preliminary trial. Am J Ophthalmol 2007; 144(1):139–141.
45.Wu W, Drenser KA, Capone A, et al. Plasmin enzyme-assisted vitreoretinal surgery in congenital X-linked retinoschisis: Surgical techniques based on a new classification system. Retina 2007;27(8):1079–1085.
46.Pilli S, Kotsolis A, Spaide RF, et al. Endophthalmitis associated with anti-vascular endothelial growth factor therapy injections in an office setting. Am J Ophthalmol 2008;145:878–882.
330
CHAPTER
48
The use of vital dyes during vitreoretinal
surgery – chromovitrectomy
Michel Eid Farah, MD, Maurício Maia, MD, PhD, Fernando M. Penha, MD, PhD, and Eduardo Büchele Rodrigues, MD
KEY FEATURES, INTRODUCTION, AND HISTORY
The term “chromovitrectomy” refers to the use of vital dyes during vitreoretinal surgery to assist in the identification of preretinal tissues and membranes.1 The modern approach was first introduced in 2000, when the dye indocyanine green (ICG) was used to stain the thin semitransparent internal limiting membrane (ILM). Following initial experience with ICG, clinical and experimental studies demonstrated signs of the retinal toxicity of ICG, which stimulated research on alternative dyes for chromovitrectomy. Some additional alternative biostains, including trypan blue (TB), patent blue (PB), or brilliant blue (BriB), have been added to the surgical armamentarium for chromovitrectomy.2 This chapter presents the latest data on chromovitrectomy in regard to the biochemical properties, indications, and clinical experience with various vital dyes available for chromovitrectomy.
RATIONALE
The introduction of ILM peeling to treat idiopathic macular holes enhanced closure rates to approximately 95% based on recent publications, compared with 60–90% closure rates in eyes without ILM peeling. However, surgical removal of ILM could lead to anatomic and functional retinal damage, and the two main postoperative clinical signs of complications of ILM removal are: (1) visual field defects and (2) retinal pigmented epithelium (RPE) damage.3
The basic rationale for the application of dyes during vitreoretinal surgery is that simple, preretinal membranes and tissues such as the ILM are very thin and semitransparent and thus difficult to detect. The application of dyes during vitreoretinal surgery indeed improved the visualization of several thin and transparent tissues in the vitreoretinal interface, such as the ILM.
PHARMACOLOGY AND BIOCHEMISTRY
Dyes are complex organic molecules containing chromophores, chemical moieties responsible for their color. By definition, vital staining refers to the coloration of living cells or tissues. In order to evaluate the various dyes currently available, the staining agents may be classified according to several criteria, where the most commonly applied include chemical classification. Some of the groups of dyes already applied in chromovitrectomy are: (1) azo dyes; (2) arylmethane dyes; (3) cyanine dyes; (4) xanthene dyes; and (5) colored corticosteroids.
Azo dyes are a class of synthetic organic dyes with nitrogen in the azo form of −N=N− in their structure. TB is an anionic hydrophilic azo dye which has the molecular formula C34H24N6Na4O14S4 and a molecular weight of 960 Da. TB crosses the cell membranes of dead cells only, thereby staining dead tissues/cells blue. The application of TB in ocular surgery has been widespread for vitrectomy and cataract surgery. For chromovitrectomy, TB may be commercially available at a concentra-
tion of 0.15% for vitreoretinal surgery, called Membrane Blue (DORC International, Zuidland, Netherlands).
Cyanine dyes are a class of dyes containing a −CH= group linking two heterocyclic rings containing nitrogen. ICG is a tricarbocyanine anionic vital dye with a molecular formula of C43H47N2NaO6S2 and a molecular weight of 775 Da. The cyanine agent has amphiphilic properties and thereby binds to both cellular and acellular elements in living tissues. The hydrophilic dye is provided as a sterile powder and represents a very useful contrast agent in angiography, allowing imaging of choroidal and retinal tissues. For ophthalmology, ICG is commercially available under the names of ICG-Pulsion (Pulsion Medical Systems, Munich, Germany; 25and 50-mg vials), ICV Indocianina Verde (Ophthalmos, São Paulo, Brazil; 5-, 25-, and 50-mg vials), Diagnogreen (Daiichi Pharmaceutical, Tokyo, Japan; 25-mg vial), and IC-Green (Akorn, Buffalo Grove, USA; 25-mg vial). The dye is commercially provided as a powder in the above amounts (from 5 to 50 mg) to achieve final concentrations of 0.05–0.5%. Infracyanine green (IfCG) is a green dye with the same chemical formula and similar pharmacologic properties as ICG. IfCG is commercially available under the brand name of Infracyanine (Laboratoires SERB, Paris, France; 25-mg vial), it contains no sodium iodine in the final solution and its final dilution in 5% glucose produces an iso-osmotic solution of around 310 mmol/kg.
Arylmethane dyes are a group of stains which are formed by one carbon linked to benzene or naphthalene groups; they are commonly used in modern inks. BriB is a blue anionic arylmethane compound which has the chemical formula of C47H48N3S2O7Na and a molecular weight of 854 Da. Animal and human data on the use of BriB for application in vitreoretinal surgery and anterior lens capsule staining have been described. The dye gained approval for intraocular use in Europe in 2007 under the brand name of Brilliant Peel (Geuder, Heidelberg, Germany), and it is provided in vials containing 2 mg/ml of the vital dye. Bromophenol blue (BroB) is another arylmethane color marker dye with a molecular weight of 670 Da and the chemical formula of C19H10Br4O5S. BroB has been applied in ocular surgery: the dark-blue stain may represent a novel useful adjunct for both cataract and vitreoretinal surgery, although there is no commercially available product in the USA. PB is a hydrophilic anionic triarylmethane dye with the chemical formula of C27H31N2NaO6S2 and a molecular weight of 582 Da. PB has been certified in Europe since 2003 for capsule staining in cataract surgery in a ready-to-use solution at a concentration of 0.24% under the brand name of Blueron (Geuder, Heidelberg, Germany), whereas it has also been applied as an off-label agent in vitreoretinal surgery.
The term “xanthenes” may be applied to yellow heterocyclic organic compounds with the chemical formula C13H10O. Xanthene molecule is the basis of xanthene dyes; for instance, fluorescein is derived from its structure. Fluorescein is a xanthene fluorophore with the chemical structure C20H12O5 and a molecular weight of 332 Da. Fluorescein may be found in nature conjugated with over 50 salt molecules or derivates, including fluorescein sodium (FS) and fluorescein diacetate (FD). Fluorescein is used extensively as a diagnostic tool in the field of ophthalmology mainly as FS, while for ocular surgery the xanthene compound has been shown to stain the vitreous gel in the form of either FS or FD.
Corticosteroids are hormones produced naturally in the cortex of the adrenal gland, whose derivates may be synthetically produced to be
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