Mark H. Criswell

Corticosteroids in posterior segment disease: an update on new delivery systems and new indications.

Purpose of review Corticosteroids are traditionally used for inflammatory disorders because of their ability to diminish neutrophil transmigration, limit access to sites of inflammation, and decrease cytokine production. More recently, however, investigators have focused on the angiostatic and antipermeability properties of corticosteroids for posterior segment diseases such as age-related macular degeneration (AMD), diabetic retinopathy, and macular edema. Both new angiostatic and traditional corticosteroids are currently undergoing evaluation as new delivery techniques such as intravitreal injection and intraocular sustained-release devices facilitate high local angiostatic and antipermeability concentrations while minimizing extraocular toxicity. The purpose of this review is to discuss recent work concerning both the mechanism and effectiveness of these newer treatments. Recent findings Steroids may exert a beneficial effect in AMD–related choroidal neovascular membranes (CNVM) through inhibition of CNVM-promoting macrophages and direct inhibition of angiogenic growth factors. They may also alter extracellular matrix turnover and inhibit matrix metalloproteinases involved in CNVM formation. Intravitreal steroid injections potently inhibit experimental CNVM in primates and rats and have shown promise in some early human pilot trials. In proliferative diabetic retinopathy, steroids may directly inhibit growth factors such as vascular endothelial derived growth factor and inhibit leukocytes that play an important role in early microvascular alterations. Intravitreal steroid injections inhibit experimental preretinal neovascularization in pigs and rats, and rubeosis in some early human studies. In addition, the effect of steroids on vascular permeability has led to their use for macular edema from many causes such as diabetes and venous occlusive disease. Summary The use of steroids to treat a number of retinal diseases is gaining wide spread acceptance. The apparent short-term success must be balanced by the fact that the long-term safety and efficacy have yet to be determined for any of these approaches. A number of large randomized prospective clinical trials of steroid compounds and new delivery systems are currently under way for AMD, diabetic retinopathy, uveitis, and other retinovascular diseases, and hopefully these studies will provide guidance about the use of these new modalities.

Squalamine lactate reduces choroidal neovascularization in a laser-injury model in the rat.

Purpose To determine if systemically administered squalamine lactate, a novel aminosterol with antineoplastic and antiangiogenic activity, inhibits the development of experimental choroidal neovascularization membranes (CNVMs) induced by laser trauma in a rat model. Methods Twenty anesthetized male Brown-Norway rats received a series of 8 krypton red laser lesions per eye (647 nm, 0.05 second, 50 &mgr;m, 150 mW). One half the animals received an intraperitoneal injection of squalamine and the other one half received an injection of 5% dextrose in water, all performed in a masked fashion. Fundus photography and fluorescein angiography were performed at postlaser treatment days 14 and 28, and ocular tissues were processed for light microscopic examination following euthanasia of the rats on postlaser treatment day 28. Results Although fundus photography and fluorescein angiography yielded no statistically significant quantitative differences between the two groups, histologic analysis of the lesion sites revealed a partial but statistically significant reduction of experimental CNVM development in the squalamine-treated population. In particular, the squalamine-treated eyes (n = 20) demonstrated lesions (n = 149) with a mean CNVM thickness ± SD of 47 ± 11 &mgr;m, as compared with the control eyes (n = 20) that had lesions (n = 142) with a mean CNVM thickness ± SD of 63 ± 14 &mgr;m (P < 0.001). Conclusion Systemically administered squalamine lactate partially reduced choroidal neovascular membrane development induced by laser trauma in this animal model. In conjunction with other existing and developing therapies, this agent may have a potential role in the treatment of human CNVM formation. Further study of squalamine lactate for treatment of neovascular eye disease is warranted.

Current and Future Treatment Options for Nonexudative and Exudative Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in the industrialised world. Although relatively simple to diagnose through direct visualisation augmented with rapid sequence fluorescein angiography, treatment has presented a far greater challenge because the true aetiology of AMD is largely unknown. Within the past decade, researchers have introduced many new, potentially promising treatment and prevention options in an attempt to minimise the damage imparted from AMD. They capitalise on many of the theoretical and known factors contributing to AMD progression. A high-dose of an orally administered combination of the antioxidants ascorbic acid (vitamin C), tocopherol (vitamin E) and β-carotene, in addition to copper and zinc, is the only widely accepted preventive therapy. Thermal laser photocoagulation and verteporfin photodynamic therapy are the only standard treatment options available based on large scale, randomised, prospective, placebo-controlled trials; however, efficacy is limited and only a minority of patients who present with AMD are eligible for these treatments. Many other preventive and treatment options are in all phases of clinical studies and expected to change the entire approach to AMD management in the near future. For example, alternative antioxidants, drusen ablation, apheresis and HMG-CoA reductase inhibitors have shown promise in some studies by preventing or slowing the progression of certain forms of AMD. In addition, alternative photodynamic therapies, low-intensity laser, antiangiogenic medications, radiation treatment and surgery have demonstrated the ability, albeit to differing degrees, to inhibit or possibly even reverse the severe vision loss often associated with AMD characterised by choroidal neovascularisation.

An update on photodynamic therapy in age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of irreversible loss of central vision in people aged > 50 years in the western world. Until recently, the only proven treatment to reduce the risk of vision loss from its more severe neovascular form was laser photocoagulation, but this treatment was suitable for only 15% of cases. Photodynamic therapy (PDT) with verteporfin was recently proposed to be effective in reducing the risk of visual loss for an estimated 20 – 30% of neovascular AMD patients. This review covers AMD epidemiology, the mechanism of PDT, the 2-year results of the two major clinical studies of PDT with verteporfin, the cost-effectiveness of PDT and the current research status of other drugs for PDT in AMD.

Pharmacologic therapy for diabetic retinopathy.

Diabetic retinopathy remains one of the major causes of acquired blindness in developed nations. This is true despite the development of laser treatment, which can prevent blindness in the majority of those who develop macular oedema (ME) or proliferative diabetic retinopathy (PDR). ME is manifest by retinal vascular leakage and thickening of the retina. The hallmark of PDR is neovascularisation (NV) – abnormal angiogenesis that may ultimately cause severe vitreous cavity bleeding and/or retinal detachment. Pharmacologic therapy aimed specifically at preventing vascular leakage and NV would be a welcome addition to the armamentarium. PDR and ME could be prevented by improved metabolic control or by pharmacologically blunting the biochemical consequences of hyperglycaemia (e.g., with aldose reductase inhibitors, inhibitors of non-enzymatic glycation or by protein kinase C [PKC] inhibition). The angiogenesis in PDR could be treated via growth factor (e.g., vascular endothelial growth factor [VEGF], insulin like growth factor-1 [IGF-1]) blockade, integrin (e.g., alpha-v beta-3) blockade, extracellular matrix alteration (e.g., with steroid compounds) or interference with intracellular signal transduction pathways (e.g., PKC and mitogen activated protein kinase [MAPK] pathway proteins). Some of these antiangiogenic agents may also prove useful for treating or preventing ME. Numerous potentially useful antiangiogenic compounds are in development; two drugs are presently in clinical trials for treatment of the preproliferative stage of PDR, while two are in clinical trials for treatment of ME.

ORAL ADMINISTRATION OF LUMIRACOXIB REDUCES CHOROIDAL NEOVASCULAR MEMBRANE DEVELOPMENT IN THE RAT LASER-TRAUMA MODEL

Purpose: To determine whether lumiracoxib, a highly selective cyclooxygenase-2 (COX-2) inhibitor that exhibits anti-inflammatory and antiangiogenic properties, can inhibit experimental choroidal neovascular membrane (CNVM) development induced by focal laser trauma in a well-characterized Brown Norway rat CNVM model. Methods: Over a 35-day period, 24 rats received daily oral gavage dosages of 20 mg/kg lumiracoxib in a 0.5% (w/v) suspension of sodium carboxymethylcellulose (CMC), while a control group received the 0.5% CMC suspension only. After 7 days, eight laser photocoagulation sites were placed concentrically around the optic disk to induce CNVMs. Thirty-five days later, fundus photography and fluorescein angiography (FA) were performed and eyes were processed for histopathologic analysis. Results: Masked FA grading of lesion sites revealed a small, but statistically significant difference (P < 0.0001) in late stage staining intensity and leakage between the mean group scores of treated (1.4) and control (1.7) eyes. Histopathologic analysis demonstrated that the mean CNVM thickness ± SD of 38 ± 19 &mgr;m (n = 24 eyes, 175 photocoagulation sites) in the lumiracoxib-treated animals was reduced by 30% (P < 0.001) compared to the CNVM mean thickness ± SD of 54 ± 20 &mgr;m (n = 24 eyes, 171 photocoagulation sites) in the control animals. Conclusion: Systemic administration of the selective COX-2 inhibitor lumiracoxib results in a partial but significant reduction in CNVM development in the rat laser-trauma model and thus may be clinically beneficial as a potential inhibitor of CNVM formation in exudative age-related macular degeneration.

Differences in the temporal expression of regulatory growth factors during choroidal neovascular development

Although the roles of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and hepatocyte growth factor (HGF) in pathologic neovascularization have been well characterized in certain tissues, their particular functions and expression patterns in choroidal neovascularization (CNV) have not been clearly established. After localized laser trauma to Bruchs membrane to induce CNV development, the temporal changes in mRNA and protein expression of these 3 cytokines were documented and compared histologically to areas of immunofluorescence, the proliferation of endothelial cells, neovascular development, and temporal changes in vascular permeability. Changes in mRNA and protein levels of bFGF and HGF occurred quickly and reached peak expression within hours. This activity corresponded in time to intense and localized immunofluorescence for these cytokines within the choriocapillaris within laser lesion sites. During this same initial time period, mRNA upregulation of VEGF occurred, primarily within the neural retina and this expression corresponded to intense immunolabeling of Müller cells immediately adjacent to the lesion sites. By 3 days after lasering, increased VEGF(164) protein expression was measurable, whereas early neovascular development histologically corresponded to HGF and bFGF mRNA expansion into the developing choroidal neovascular membrane (CNVM). At 7 days, CNV expansion, maturation, and increased vascular permeability corresponded to peak VEGF mRNA and protein expression and to immunofluorescence of the CNVM. Differences also occurred in the expression of precursor and activated isoforms of these cytokines in the retinal pigment epithelium/choroid as compared to those in the retina. These molecular and immunocytochemical results suggest that bFGF and HGF may be important as initial regulators neovascularization in this CNV model; whereas VEGF may be important during later phases of angiogenesis and neovascular hyperpermeability.

Anti-angiogenic therapy of proliferative diabetic retinopathy

Proliferative diabetic retinopathy (PDR) remains one of the major causes of acquired blindness in developed nations. This is true despite the development of laser treatment, which can prevent blindness in the majority of those who develop this complication. The hallmark of PDR is neovascularisation (NV), abnormal angiogenesis that may ultimately cause severe vitreous cavity bleeding and/or retinal detachment. Pharmacologic therapy aimed at preventing NV, as an adjunct to laser treatment, or as an alternative to laser treatment, would be a welcome addition to the armamentarium. PDR could be prevented by improved metabolic control or by pharmacologically blunting the biochemical consequences of hyperglycaemia (e.g., with aldose reductase inhibitors, inhibitors of non-enzymatic glycation or by protein kinase C (PKC) inhibition). The angiogenesis in PDR could be treated via growth factor (e.g., vascular endothelial growth factor (VEGF), insulin like growth factor-1) blockade, integrin (e.g., α-v β-3) blockade or extracellular matrix alteration (e.g., with steroid compounds), or interference with intracellular signal transduction pathways (e.g., PKC and mitogen activated protein kinase pathway proteins). Numerous potentially useful anti-angiogenic compounds are in development, but two drugs are presently in clinical trials for the treatment of the preproliferative stage of PDR.

Comparing Pegaptanib and Triamcinolone Efficacy in the Rat Choroidal Neovascularization Model

OBJECTIVE To evaluate the prophylactic effect of intravitreal pegaptanib sodium on choroidal neovascularization membrane (CNVM) development and compare its performance with that of triamcinolone acetonide. METHODS In drug-treated and control groups, CNVMs were induced by laser trauma. Immediately after undergoing the laser procedure, animals received intravitreal injections of pegaptanib sodium, 8 or 17 mug; triamcinolone acetonide, 200 mug; or a vehicle solution. After 21 days, fluorescein angiography was performed. The CNVM mean diameters and radial thicknesses were measured histologically. RESULTS Mean CNVM diameters were 10% to 13% smaller in pegaptanib-treated eyes and 43% smaller in triamcinolone-treated eyes compared with laser-only control eyes. Late-stage fluorescein angiography leakage scores, on a scale of 0 to 3, suggested a statistical difference between triamcinolone- (0.6) and pegaptanib(8 microg)-treated (1.5) groups compared with the laser-only control group (2.0). The CNVM mean thicknesses were greater in the pegaptanib(8 microg)- (79 microm) and pegaptanib(17 microg)-treated (71 microm) groups and significantly smaller in the triamcinolone-treated group (26 microm) compared with the laser-only control group (67 microm). CONCLUSION In this animal model of choroidal neovascularization, intravitreal pegaptanib exhibited marginal or no effect on CNVM development; whereas intravitreal triamcinolone evoked robust inhibition of CNVMs. Clinical Relevance Pegaptanib treatment may be insufficient to prevent CNVM formation.

Future pharmacological treatment options for nonexudative and exudative age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in the industrialised world. Within the past decade, researchers have introduced many promising prevention and treatment options in an attempt to minimise the central vision loss imparted from AMD. Based on large-scale, randomised, prospective, placebo-controlled trials, a specially formulated combination of the antioxidants vitamin C, vitamin E, β-carotene, copper and zinc is the only proven means of AMD prophylaxis. Thermal laser photocoagulation and photodynamic therapy with verteporfin are the only standard treatment options. However, efficacy is limited and treatment is only applicable to a minority of AMD patients. Thus, alternative pharmacological interventions are in all phases of clinical development. Researchers are guardedly optimistic that these advances may change the entire approach to AMD management in the near future. This review article will detail the currently accepted treatment options, as well as describe several of the more promising investigational pharmacological approaches to AMD.