Effect of Factor XIII-A G185T Polymorphism on Visual Prognosis after Photodynamic Therapy for Neovascular Macular Degeneration.

Macular degenerations represent leading causes of central blindness or low vision in developed countries. Most of these severe visual disabilities are due to age-related macular degeneration (AMD) and pathologic myopia (PM), both of which are frequently complicated by subfoveal choroidal neovascularization (CNV). Photodynamic therapy with verteporfin (PDT-V) is still employed for CNV treatment in selected cases or in combined regimen. In Caucasian patients, the common polymorphism G185T of factor XIII-A gene (FXIII-A-G185T; rs5985) has been described as predictor of poor angiographic CNV responsiveness to PDT-V. Nevertheless, the prognostic implications of this pharmacogenetic determinant on long-term visual outcome after a PDT-V regimen have not been evaluated. We retrospectively selected Caucasian patients presenting with treatment-naive CNV and receiving standardized PDT-V protocol for two years. The study population included patients affected by subfoveal CNV secondary to AMD or PM. We assessed the correlations between the polymorphic allele T of FXIII-A-G185T and: (1) total number of photodynamic treatments; and (2) change in visual acuity from baseline to the end of the follow-up period. Considering a total study population of 412 patients with neovascular AMD or PM, the carriers of 185 T-allele of FXIII-A (GT or TT genotype) received a higher number of photodynamic treatments than patients without it (GG wild-type genotype) (p < 0.01; mean number of PDT-V: 5.51 vs. 3.76, respectively). Moreover, patients with 185 T-allele of FXIII-A had a more marked worsening of visual acuity at 24 months than those with the GG-185 wild genotype (p < 0.01; mean difference in logMAR visual acuity: 0.22 vs. 0.08, respectively). The present findings show that the G185T polymorphism of the FXIII-A gene is associated with significant differences in the long-term therapeutic outcomes of patients treated with standardized PDT-V protocol. The comprehensive appraisal of both anti-thrombophilic effects due to FXIII-A G185T variant and photo-thrombotic action of PDT-V toward CNV provides several clues about the rationale of this intriguing pharmacogenetic correlation. Further investigations are warranted to outline the appropriate paradigm for guiding PDT-V utilization in the course of the combined therapeutic protocol for neovascular macular degeneration.

Mechanism of inflammation in age-related macular degeneration: an up-to-date on genetic landmarks.

Age-related macular degeneration (AMD) is the most common cause of irreversible visual impairment among people over 50 years of age, accounting for up to 50% of all cases of legal blindness in Western countries. Although the aging represents the main determinant of AMD, it must be considered a multifaceted disease caused by interactions among environmental risk factors and genetic backgrounds. Mounting evidence and/or arguments document the crucial role of inflammation and immune-mediated processes in the pathogenesis of AMD. Proinflammatory effects secondary to chronic inflammation (e.g., alternative complement activation) and heterogeneous types of oxidative stress (e.g., impaired cholesterol homeostasis) can result in degenerative damages at the level of crucial macular structures, that is photoreceptors, retinal pigment epithelium, and Bruch's membrane. In the most recent years, the association of AMD with genes, directly or indirectly, involved in immunoinflammatory pathways is increasingly becoming an essential core for AMD knowledge. Starting from the key basic-research notions detectable at the root of AMD pathogenesis, the present up-to-date paper reviews the best-known and/or the most attractive genetic findings linked to the mechanisms of inflammation of this complex disease.

Mechanism of inflammation in age-related macular degeneration.

Age-related macular degeneration (AMD) is a multifactorial disease that represents the most common cause of irreversible visual impairment among people over the age of 50 in Europe, the United States, and Australia, accounting for up to 50% of all cases of central blindness. Risk factors of AMD are heterogeneous, mainly including increasing age and different genetic predispositions, together with several environmental/epigenetic factors, that is, cigarette smoking, dietary habits, and phototoxic exposure. In the aging retina, free radicals and oxidized lipoproteins are considered to be major causes of tissue stress resulting in local triggers for parainflammation, a chronic status which contributes to initiation and/or progression of many human neurodegenerative diseases such as AMD. Experimental and clinical evidences strongly indicate the pathogenetic role of immunologic processes in AMD occurrence, consisting of production of inflammatory related molecules, recruitment of macrophages, complement activation, microglial activation and accumulation within those structures that compose an essential area of the retina known as macula lutea. This paper reviews some attractive aspects of the literature about the mechanisms of inflammation in AMD, especially focusing on those findings or arguments more directly translatable to improve the clinical management of patients with AMD and to prevent the severe vision loss caused by this disease.

Impact of coagulation-balance gene predictors on efficacy of photodynamic therapy for choroidal neovascularization in pathologic myopia.

PURPOSE: To investigate whether different coagulation-balance genetic backgrounds might explain the variable clinical outcomes detected, after a single photodynamic therapy with verteporfin (PDT-V), in Caucasian patients with subfoveal choroidal neovascularization (CNV) secondary to pathologic myopia (PM). DESIGN: Retrospective, consecutive, nonrandomized, interventional cases series. PARTICIPANTS: Two hundred thirty-four patients exclusively treated with standardized PDT-V for the presence of PM-related classic CNV. METHODS: The enrolled patients were subdivided as responders or nonresponders based on CNV responsiveness to the first PDT-V over a 3-month period. Three common gene polymorphisms, factor XIII-A G185T, methylenetetrahydrofolate reductase C677T, and methionine synthase reductase A66G, were genotyped by polymerase chain reaction in each patient. MAIN OUTCOME MEASURES: The measures of CNV responsiveness to PDT-V were the changes, respect to baseline, of fluorescein angiography CNV leakage, greatest linear dimension, and area of the lesion. Logistic regression analyses were performed to explore the predictive role of phenotypic (patient's age, baseline visual acuity, and baseline CNV area) and genotypic (all the mentioned mutations) variables regarding PDT-V efficacy. RESULTS: Responders to PDT-V were overrepresented within carriers of methylenetetrahydrofolate reductase 677 T-allele (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.8-5.4; P = 0.001) and, to a minor extent, among patients with better visual acuity at baseline (OR, 11.8; 95% CI, 1.6-88.0; P = 0.02). However, predictors of PDT-V lack of efficacy were patient's age (OR, 0.73; 95% CI, 0.62-0.86; P = 0.01) and, especially, factor XIII-A 185 GT/TT genotypes (OR, 0.19; 95% CI, 0.11-0.35; P = 0.0001). All the other considered predictive factors did not significantly influence the CNV responsiveness to PDT-V. CONCLUSIONS: These findings document the presence of pharmacogenetic correlations between common coagulation-balance gene polymorphisms and different CNV responsiveness to PDT-V in Caucasian patients with neovascular PM.

Inflammatory mediators and angiogenic factors in choroidal neovascularization: pathogenetic interactions and therapeutic implications.

Choroidal neovascularization (CNV) is a common and severe complication in heterogeneous diseases affecting the posterior segment of the eye, the most frequent being represented by age-related macular degeneration. Although the term may suggest just a vascular pathological condition, CNV is more properly definable as an aberrant tissue invasion of endothelial and inflammatory cells, in which both angiogenesis and inflammation are involved. Experimental and clinical evidences show that vascular endothelial growth factor is a key signal in promoting angiogenesis. However, many other molecules, distinctive of the inflammatory response, act as neovascular activators in CNV. These include fibroblast growth factor, transforming growth factor, tumor necrosis factor, interleukins, and complement. This paper reviews the role of inflammatory mediators and angiogenic factors in the development of CNV, proposing pathogenetic assumptions of mutual interaction. As an extension of this concept, new therapeutic approaches geared to have an effect on both the vascular and the extravascular components of CNV are discussed.

Efficacy of probing for children with congenital nasolacrimal duct obstruction: a retrospective study using fluorescein dye disappearance test and lacrimal sac echography.

PURPOSE: To evaluate B-scan echography for the assessment of lacrimal sac (LS) in pediatric epiphora secondary to congenital nasolacrimal duct obstruction (CNLDO), and to verify its predictive role in functional efficacy of nasolacrimal duct probing. PATIENTS AND METHODS: Thirty-nine eyes of 23 consecutive children, treated with a single probing for persistent CNLDO-related epiphora, were retrospectively studied. These cases were investigated both collectively and considering two sub-groups: group A (ten patients [20 eyes] 13 months. Fluorescein dye disappearance test at 10 minutes (FDDT-10) and ultrasound examination of LS were performed before and after probing. An echographic LS scoring system (grade 0 = no LS enlargement; grade 1 = slight longitudinal LS enlargement; grade 2 = longitudinal and slight transverse LS enlargement; grade 3 = marked longitudinal and transverse LS enlargement) was introduced as a predictor of probing efficacy, estimating FDDT-10 modification between pre- and post-operative checks. RESULTS: Echographic LS evaluation was easily practicable without sedation. In the total cluster and in both age sub-groups, post-probing FDDT-10 decreased with respect to pre-probing value (p < 0.001). Post-probing LS score improved with respect to pre-probing check within the total cluster and group A (p < 0.05). Strong correlation between pre-probing LS alteration and functional probing failure was present in each studied cluster (all p values <0.0001). Within group B, a greater gain of post-probing FDDT-10 was more frequent in patients with a better pre-probing LS score, as well as in younger children (both p values <0.0001). CONCLUSIONS: In children with CNLDO-related epiphora, B-scan echography of the LS can represent a reliable and useful examination for a better understanding of the functional prognosis after probing treatment.

Increased retinal blood flow in patients with active Graves' ophthalmopathy.

PURPOSE: To investigate retinal blood flow by Heidelberg retina flowmeter in patients with active Graves' ophthalmopathy. MATERIALS AND METHODS: Thirty patients with active Graves' ophthalmopathy in euthyroid state and thirty normal controls were enrolled in this study. All subjects underwent heart rate, systolic and diastolic blood pressure detection, complete ophthalmological examination, Hertel's exophthalmometry, and retinal blood flow analysis by Heidelberg retina flowmeter. Patients additionally underwent automated threshold perimetry and extraocular muscle thickness measurement by A-scan ecography. RESULTS: A significant statistical difference was found in exophthalmometry (P<0.001), intraocular pressure (P<0.001) and retinal blood flow (P<0.05) between patients and controls. In patients, muscle enlargement was significantly correlated with retinal blood flow (r=0.49, P=0.005) and proptosis (r=0.37, P=0.04). A significant positive correlation (r=0.52, P=0.002) was also found between intraocular pressure and proptosis. CONCLUSIONS: Active Graves' ophthalmopathy patients present an increased retinal blood flow.

Evaluation of a Real-time PCR-based assay using the lightcycler system for detection of Toxoplasma gondii bradyzoite genes in blood specimens from patients with toxoplasmic retinochoroiditis.

PCR based methods have advantages over traditional methods for the diagnosis of toxoplasmosis, especially when serology fails and clinical symptoms are not evident. However, current PCR-based assays are often labour-intensive and not readily quantifiable and have the potential for contamination due to a requirement for postamplification sample handling. Real-time PCR can address these limitations. We have developed and evaluated a highly sensitive Real-time PCR (Light-cycler, LC-PCR) to detect and quantify Toxoplasma gondii B1 and bradyzoite specific genes (SAG-4, MAG-1) in serum and peripheral blood mononuclear cells (PBMC) specimens, from five immunocompetent subjects with clinically suspected toxoplasmic retinochoroiditis (TRC) or without a suspected T. gondii infection. A standard curve for quantitation of parasitic load was generated using SYBR Green I fluorescent detection. The results were compared with those obtained with a nested PCR (n-PCR). In TRC patients, both PCR methods confirmed ophtalmoscopy and fluorangiographic findings. Among the TRC patients, the use of LC-PCR was more sensitive than n-PCR for detection and quantification of either B1 gene (P<0.001) or SAG-4/MAG-1 gene (P<0.05). LC-PCR has been shown particularly useful to accurately determine the parasite DNA load in follow-up specimens in whom the performance of either B1 or SAG-4 and MAG-1 in detecting T. gondii loads, varied with respect to specific antitoxoplasmic treatment.

Does Insulin Like Growth Factor-1 (IGF-1) Deficiency Have a "Protective" Role in the Development of Diabetic Retinopathy in Thalassamia Major Patients?

RATIONALE: Both insulin and IGF-1 have been implicated in the control of retinal endothelial cell growth, neovascularization and diabetic retinopathy. Recent findings have established an essential role for IGF-1 in angiogenesis and demonstrated a new target for control of retinopathy that explains why diabetic retinopathy initially increases with the onset of insulin treatment. OBJECTIVE: This cross-sectional study was designed to give insights into relationship between Insulin-Growth-Factor 1 (IGF-1) levels and diabetic retinopathy (DR) in a sample of thalassemia major (TM) patients with insulin dependent diabetes mellitus (IDDM). This relation was not previously evaluated, despite the fact that both diseases co-exist in the same patient. The study also describes the clinical and biochemical profile of the associated complications in TM patients with and without IDDM. DESIGN: A population-based cross-sectional study. PARTICIPANTS: The study includes 19 consecutive TM patients with IDDM and 31 age- and sex-matched TM patients without IDDM who visited our out-patient clinics for an endocrine assessment. METHODS: An extensive medical history, with data on associated complications and current medications, was obtained. Blood samples were drawn in the morning after an overnight fast to measure the serum concentrations of IGF-1, glucose, fructosamine, free thyroxine (FT4), thyrotropin (TSH) and biochemical analysis. Serologic screening assays for hepatitis C virus seropositivity (HCVab and HCV-RNA) were also evaluated; applying routine laboratory methods. Plasma total IGF-1 was measured by a chemiluminescent immunometric assay (CLIA) method. Ophthalmology evaluation was done by the same researcher using stereoscopic fundus biomicroscopy through dilated pupils. DR was graded using the scale developed by the Global Diabetic Retinopathy Group. Iron stores were assessed by direct and indirect methods. RESULTS: Eighteen TM patients with IDDM (94.7 %) and ten non-diabetic patients (32.2 %) had IGF-1 levels below the 2.5(th) percentile of the normal values for the Italian population. The mean serum IGF-1 concentrations were significantly lower in the diabetic versus the non-diabetic TM groups (p < 0.001). DR was present in 4 (21 %) of 19 TM patients with IDDM and was associated with the main classical risk factors, namely inefficient glycemic control and duration of the disease but not hypertension. Using the scale developed by the Global Diabetic Retinopathy Group, the DR in our patients was classified as non proliferative diabetic retinopathy (NPDR). Only a few numbers of microaneurysms [1-3] were detected. Our data also confirm the strong association of IDDM in TM patients with other endocrine and non-endocrine complications.

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency associated with bilateral keratoconus.

PURPOSE: To report a clinical association between congenital adrenal hyperplasia and keratoconus. DESIGN: Observational case report. METHODS: Two 25-year-old dizygotic female twins were retrospectively studied. Clinical history, hormonal serologic profile, complete ophthalmologic examination, and Holladay Diagnostic Summary variables were evaluated. In the course of a 15-month follow-up period, a progression of the corneal disease was observed. RESULTS: In both twins a diagnosis of nonclassical congenital adrenal hyperplasia, due to 21-hydroxylase deficiency, was established when they were 21 years old. In one subject, the computed corneal topographic analyses diagnosed an asymmetric keratoconus in both eyes. A progressive form of fruste central keratoconus was also documented in her sister. CONCLUSIONS: Congenital adrenal hyperplasia may be associated with keratoconus. An abnormal steroidogenic pathway, affecting the normal development of the cornea, could induce stromal abnormalities that lead to corneal ectasia.

Recurrent episodes of spontaneous subconjunctival hemorrhage in patients with factor XIII Val34Leu mutation.

PURPOSE: To report on the occurrence of frequent episodes of spontaneous subconjunctival hemorrhage (SCH) in patients with the Leu 34 allele of the coagulation factor XIII (FXIII), known to be associated with high hemorrhagic risk. DESIGN: Observational case series. METHODS: Five young adults who had suffered from recurrent idiopathic SCH not associated with any recognized ocular and systemic hemorrhagic risk factor were investigated. Accurate anamnestic, ophthalmologic, hematologic, and serologic examinations were performed, together with blood pressure measurements, electrocardiogram (ECG), and 24-hour Holter ECG recordings. FXIII Val34Leu polymorphism was studied by DNA chain polymerase reaction. RESULTS: DNA analyses showed that the hemorrhagic mutated Leu34 allele was present in four of our selected patients: two mutated homozygotes (Leu/Leu) and two heterozygotes (Val/Leu). In the last subject this polymorphism was not detected. All the other clinical evaluations did not disclose any significant abnormality. CONCLUSIONS: The FXIII Val34Leu mutation may be associated with an increased risk for spontaneous episodes of SCH.

Prevalence of factor XIII Val34Leu polymorphism in patients affected by spontaneous subconjunctival hemorrhage.

PURPOSE: To verify the prevalence of Val34Leu polymorphism in factor XIII A-chain gene (FXIII Val34Leu) in patients with spontaneous subconjunctival hemorrhage (SCH). DESIGN: Nonrandomized case-control study. METHODS: One hundred seven white patients suffering from one or more episodes of idiopathic SCH and 107 healthy subjects were matched for age and gender, and genotyped for FXIII Val34Leu. Anamnestic, ophthalmologic, cardiovascular, and serologic examinations were performed. RESULTS: Frequency of FXIII mutated allele (Leu34) was significantly higher in SCH patients than in controls. Computing together heterozygotes (Val/Leu) and homozygotes (Leu/Leu), genotype distribution was statistically different. In a conditional logistic regression model, the comparison of the three separated genotypes, performed among 25 patients with recurrent idiopathic SCHs and controls, gave significant differences for both Val/Leu and Leu/Leu variables. CONCLUSION: Both homozygosity and heterozygosity for FXIII Val34Leu predispose to idiopathic SCH, emphasizing the role of Leu34 allele as inherited risk factor for spontaneous, especially recurrent, SCHs.

Mesectodermal leiomyoma exclusively involving the posterior choroid.

PURPOSE: To report a mesectodermal leiomyoma of the posterior choroid. DESIGN: Observational case report. METHODS: A 23-year-old man was referred to us because of a progressive blurred vision in his left eye. Ophthalmologic examination revealed the presence of a 12 x 10 x 7.2-mm amelanotic choroidal mass in his left posterior pole. Fluorescein angiography, A-scan ultrasonography, and B-scan echography findings were suggestive for a diagnosis of choroidal amelanotic melanoma. These clinical features prompted us to enucleate the left eye. RESULTS: Histopathological and immunohistochemistry examinations established a definitive diagnosis of mesectodermal leiomyoma of the posterior choroid. CONCLUSION: This case represents the first report describing the occurrence of an intraocular mesectodermal leiomyoma that may exclusively involve the posterior choroid.

Pharmacogenetic aspects in therapeutic management of subfoveal choroidal neovascularisation: role of factor XIII-A 185 T-allele.

In Western Countries, the occurrence of choroidal neovascularization (CNV) secondary to different forms of macular degeneration represents a common cause of blindness. Particularly, age-related macular degeneration (AMD) and pathologic myopia (PM) are the most frequent diseases related to CNV development. At present, the combined employment of drugs acting against vascular endothelial growth factor (anti-VEGF) and photodynamic therapy with verteporfin (PDT-V) is a promising therapeutic strategy for neovascular macular degenerations. However, this approach inevitably leads to an increase in health-resource utilization. In several clusters of patients treated for CNV, correlations among common gene polymorphisms implicated in coagulation- or complement-cascade and different levels of, respectively, post-PDT-V or post-anti-VEGF benefit have been reported. Factor XIII-A G185T substitution (rs5985), a frequent anti-thrombophilic genetic variant of Caucasian ethnic groups, unequivocally influences a worsening of the CNV responsiveness to PDT-V in patients affected by either AMD- or PM-related CNV. These coherent pharmacogenetic findings point out the opportunities to: i. optimize the eligibility criteria of PDT-V and, ii. customize the interventional strategy against CNV, for finally minimizing the socio-economic burden of neovascular macular degenerations.

Genetic predictors of response to photodynamictherapy.

In Western countries, therapeutic management of patients affected by choroidal neovascularization (CNV) secondary to different typologies of macular degeneration represents a major health care problem. Age-related macular degeneration is the disease most frequently associated with CNV development. Schematically, CNVs can be distinguished into classic and occult subtypes, which are characterized by variable natural history and different responsiveness to some therapeutic procedures. At present, the dramatic vision loss due to CNV can be mainly treated by two interventional strategies, which are utilizable in either single or combined modalities: photodynamic therapy with verteporfin (PDT-V), and intravitreal administration of drugs acting against vascular endothelial growth factor. The combined use of PDT-V and anti-angiogenic drugs represents one of the most promising strategies against neovascular macular degeneration, but it unavoidably results in an expensive increase in health resource utilization. However, the positive data from several studies serve as a basis for reconsidering the role of PDT-V, which has undergone a renaissance prompted by the need for a more rational therapeutic approach toward CNV. New pharmacogenetic knowledge of PDT-V points to exploratory prospects to optimize the clinical application of this intriguing photothrombotic procedure. In fact, a Medline search provides data regarding the role of several single nucleotide polymorphisms (SNPs) as genetic predictors of CNV responsiveness to PDT-V. Specifically, correlations between SNPs and different levels of PDT-V efficacy have been detected by examining the gene variants influencing (i) thrombo-coagulative pathways, i.e. methylenetetrahydrofolate reductase (MTHFR) 677C>T (rs1801133), factor V (F5) 1691G>A (rs6025), prothrombin (F2) 20210G>A (rs1799963), and factor XIII-A (F13A1) 185G>T (rs5985); (ii) complement activation and/or inflammatory processes, i.e. complement factor H (CFH) 1277T>C (rs1061170), high-temperature requirement factor A1 (HTRA1) promoter -512G>A (rs11200638), and two variants of the C-reactive protein (CRP) gene (rs2808635 and rs876538); and (iii) production and bioavailability of vascular endothelial growth factor (VEGFA -2578C>A [rs699947] and rs2146323). This article critically evaluates both the clinical plausibility and the opportunity to utilize the most important SNP-response interactions of PDT-V for an effective upgrade of the current anti-CNV therapeutic scenario. In addition, the pharmacogenetics of a very severe post-PDT-V adverse event, i.e. a decrease in acute vision, is briefly discussed. A comprehensive appraisal of the findings reviewed in this article should be carefully considered to design future trials aimed at verifying (after proper genotypic stratification of the enrolled patients) whether these innovative pharmacogenetic approaches will be able to improve the multifaceted interventional management of neovascular macular degeneration.

Parnaparin versus aspirin in the treatment of retinal vein occlusion. A randomized, double blind, controlled study.

INTRODUCTION: Retinal vein occlusion (RVO) is a common cause of unilateral visual loss. Evidence based treatment recommendations for patients with RVO cannot be made because of the lack of adequate clinical trials. To compare the efficacy and safety of aspirin and of a low molecular weight heparin, parnaparin, in the treatment of RVO. MATERIALS AND METHODS: In a multicenter, randomized, double blind, controlled trial eligible patients with a delay between symptoms onset and objective diagnosis of less than 15 days were randomized to aspirin 100 mg/day for 3 months or to a fixed daily dose of parnaparin, 12.800 IU for 7 days followed by 6.400 IU for a total of 3 months. Primary end-point of the study was the incidence of functional worsening of the eye with RVO at 6 months, as assessed by fluorescein angiography, visual acuity, and visual field. Study end-points were adjudicated by an independent committee. RESULTS: Sixty-seven patients were enrolled in the study and 58 of them (28 treated with parnaparin, 30 with aspirin) were evaluable for the analysis. Baseline characteristics were well balanced between groups. Functional worsening was adjudicated in 20.7% of patients treated with parnaparin and in 59.4% of patients treated with ASA (p=0.002). Recurrent RVO was diagnosed in 3 patients, all treated with ASA (p=n.s.). Bleeding rates were similar between the two groups. CONCLUSIONS: Parnaparin appears to be more effective than aspirin in preventing functional worsening in patients with RVO. The results of this study need to be confirmed in a larger clinical trial.

Predictive role of C677T MTHFR polymorphism in variable efficacy of photodynamic therapy for neovascular age-related macular degeneration.

Age-related macular degeneration (AMD) complicated by subfoveal choroidal neovascularization (CNV) is the leading cause of severe central blindness in developed countries. AMD-related CNVs are distinguishable in classic and occult subtypes, characterized by variable natural history and different responsiveness to therapeutic procedures. Combined and repeated use of photodynamic therapy with verteporfin (PDT-V) and antiangiogenic drugs represents the most promising strategy against neovascular AMD, but it is unavoidably associated with mounting health-resource utilization. Predictive correlations between peculiar coagulation-balance gene variants and different levels of post-PDT-V benefit have recently been documented in Caucasians with AMD-related CNVs. In particular, methylenetetrahydrofolate reductase C677T substitution, a common thrombophilic folate pathway genotypic polymorphism, influences a better CNV responsiveness to PDT-V in classic- but not in occult-CNV cases. These pharmacogenetic findings indicate the opportunities to optimize the eligibility criteria of PDT-V and/or to perform this intriguing therapy in a customized manner, for finally minimizing the socio-economic burden of neovascular AMD.

Predictive role of gene polymorphisms affecting thrombin-generation pathway in variable efficacy of photodynamic therapy for neovascular age-related macular degeneration.

Age-related macular degeneration (AMD) represents the leading cause of central blindness in developed countries. The majority of severe vision loss occurs in the neovascular form of AMD, generally characterized by the presence of choroidal neovascularization (CNV) beneath the fovea. Photodynamic therapy with verteporfin (PDT-V) and drugs acting against vascular endothelial growth factor are the most commonly employed treatments for AMD-related subfoveal CNV. The combined use of both these strategies is the most promising therapeutic approach towards this harmful disease. The therapeutic action of PDT-V depends to a photochemical perturbation of thrombo-coagulative processes within CNV. Predictive correlations between peculiar coagulation-balance gene polymorphisms and different levels of post-PDT-V benefit have been recently documented in Caucasian patients with neovascular AMD. Particularly, heterozygous A-allele carriers of factor V Leiden 1691 or prothrombin 20210 gene are characterized by a greater possibility to exhibit clinical benefit after PDT-V. Both mutations induce thrombophilia increasing the thrombin generation in plasma and, thus, they can consistently intensify the photothrombotic phase of the therapeutic CNV occlusion. In prospect, considering the different individual susceptibility to PDT-V, a preoperative assessment of the genotypic thrombophilic background could optimize the eligibility criteria of this intriguing treatment. This review summarizes some of the recent published patents on treatment of neovascular AMD, with a particular attention to PDT-V application in combined therapeutic modalities.

Topical and oral ketorolac administration increases the intraocular pressure-lowering effect of latanoprost.

PURPOSE: To verify the influence of a non-steroidal anti-inflammatory drug (NSAID), ketorolac (topical and oral) on the intraocular pressure reduction induced by 0.005% latanoprost topical administration, both in patients affected by primary open-angle glaucoma and in healthy controls. METHODS: Two groups of subjects were enrolled for this randomized, prospective, masked clinical study: 16 glaucomatous patients well controlled with 0.005% latanoprost eyedrops (group I) and 16 healthy adult volunteers (group II). Group I subjects were treated at one-week intervals with 10 mg of oral ketorolac, oral placebo, topical ketorolac, and topical placebo, respectively; for each administration modality, the switch between drug and placebo was performed in a randomized, crossover, double-blind fashion. Group II subjects followed the same protocol, with the topical once-daily 0.005% latanoprost treatment starting three days prior to the ketorolac/placebo administration. Intraocular pressure (IOP) was investigated in both groups on the day of oral/topical administration of ketorolac or placebo at baseline (8:00 AM) and at the following intervals: 1, 2, 4, 8, 12, and 24 hours. RESULTS: No significant IOP changes after oral and topical placebo administration were observed in either group. In contrast, when the subjects received ketorolac (either oral or topical), a marked decrease in IOP was recorded, with a noticeable fall at the first hour after the NSAID administration (p = 0.01), which remained still significant 8 hours later (p < 0.05). CONCLUSION: Topical and oral ketorolac strengthens the latanoprost-induced IOP-lowering effect both in glaucomatous patients and in healthy subjects.