Relationships between Patient-Reported Outcome Measures and Clinical Measures in Naïve Neovascular Age-Related Macular Degeneration Patients Treated with Intravitreal Ranibizumab.

Our objective was to evaluate changes in patient-reported outcome measures using the NEI-VFQ 25 questionnaire during a treat and extend regimen in naive neovascular Age-Related Macular Degeneration patients, and its correlation with anatomical and functional data. We conducted a prospective observational study. Patients underwent a treat and extend regimen with intravitreal ranibizumab for neovascular Age-Related Macular Degeneration. Initial response was evaluated at 4th month, and subsequently in every follow-up visit. If a clinical response was achieved, the injection interval was extended in two-week increments, up to a maximum of 12 weeks. Quality of life was assessed using the NEI-VFQ 25 questionnaire at baseline, 4th months, and 12th months. Patients were categorized as good or poor responders based on Best corrected visual acuity, central foveal thickness, intraretinal fluid, or subretinal fluid. Treatment with ranibizumab led to a significant improvement in quality of life, with a mean increase in NEI-VFQ 25 score of 4.27 points in the 12th month. No significant differences in improvement were observed between good and poor responders. Quality of life scores in neovascular Age-Related Macular Degeneration patients improved with intravitreal treatment regardless of the clinical response. The early response following the loading phase could indicate better quality of life after one year of treatment, with Best corrected visual acuity being the clinical parameter with the greatest influence on quality of life.

The Effect of Systemic Parameters and Baseline Characteristics in Short-Term Response Analysis with Intravitreal Ranibizumab in Treatment-Naive Patients with Neovascular Age-Related Macular Degeneration.

Anti-vascular endothelial growth factor drugs keep being the main therapy for neovascular age-related macular degeneration (AMD). Possible predictive parameters (demographic, biochemical and/or inflammatory) could anticipate short-term treatment response with ranibizumab. 46 treatment-naive patients were included in a prospective observational study. They underwent three monthly injections of intravitreal ranibizumab for neovascular AMD and the clinical examination was made at baseline and one month after the third injection. Demographic characteristics, co-morbidities and concomitant treatments were recorded at the baseline visit. Biochemical parameters, complete blood count and inflammation biomarkers were also measured at these times. Uric Acid was found to be statistically significant with a one-point difference between good and poor responders in both basal and treated patients, but only in basal parameters was statistical significance reached (p = 0.007 vs. p = 0.071 in treated patients). Cholesterol and inflammatory parameters such as white blood cell count and neutrophils were significantly reduced over time when treated with intravitreal ranibizumab. On the other hand, women seemed to have a worse prognosis for short-term response to intravitreal ranibizumab treatment. Uric acid may help identify possible non-responders before initial treatment with ranibizumab, and cholesterol and white blood cells could be good candidates to monitor short-term response to ranibizumab treatment.

Influence of Genetic Polymorphisms on the Short-Term Response to Ranibizumab in Patients With Neovascular Age-Related Macular Degeneration.

Purpose: To determine whether genetic risk single nucleotide polymorphisms (SNPs) for age-related macular degeneration (AMD) influence short-term response to intravitreal ranibizumab treatment. Methods: Forty-four treatment-naive AMD patients were included in a prospective observational study. They underwent three monthly injections of intravitreal ranibizumab for neovascular AMD. After an initial clinical examination (baseline measurement), a follow-up visit was performed to determine treatment response one month after the third injection (treatment evaluation). Patients were evaluated based on ophthalmoscopy, fluorescein angiography, optical coherence tomography (OCT), and OCT angiography. Peripheral venous blood was collected for DNA analysis at baseline visit. Patients were genotyped for single-nucleotide polymorphisms within AMD-relevant genes and classified on good or poor responders based on visual acuity, central retinal thickness, intraretinal fluid, and subretinal fluid. Results: One hundred ten AMD-associated SNPs have been analyzed. Six were found to be relevant when associated to ranibizumab treatment response. The genetic variants rs890293 (CYP2J2), rs11200638 (HTRA1), rs405509 (APOE), rs9513070 (FLT1), and rs8135665 (SLC16A8) predisposed patients to a good response, whereas rs3093077 (CRP) was associated with a poor response. FTL1, SLC16A8, and APOE were the SNPs that showed significance (P < 0.05) but did not pass Bonferroni correction. Conclusions: This is the first study that links novel polymorphisms in genes such as CRP, SCL16A8, or CYP2J2 to treatment response to ranibizumab therapy. On the other hand, HTRA1, FLT1, and APOE are linked to a good ranibizumab response. These SNPs may be good candidates for short-term treatment response biomarkers in AMD patients. However, further studies will be necessary to confirm our findings.

Recent Advances in Proteomics-Based Approaches to Studying Age-Related Macular Degeneration: A Systematic Review.

Age-related macular degeneration (AMD) is a common ocular disease characterized by degeneration of the central area of the retina in the elderly population. Progression and response to treatment are influenced by genetic and non-genetic factors. Proteomics is a powerful tool to study, at the molecular level, the mechanisms underlying the progression of the disease, to identify new therapeutic targets and to establish biomarkers to monitor progression and treatment effectiveness. In this work, we systematically review the use of proteomics-based approaches for the study of the molecular mechanisms underlying the development of AMD, as well as the progression of the disease and on-treatment patient monitoring. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) reporting guidelines were followed. Proteomic approaches have identified key players in the onset of the disease, such as complement components and proteins involved in lipid metabolism and oxidative stress, but also in the progression to advanced stages, including factors related to extracellular matrix integrity and angiogenesis. Although anti-vascular endothelial growth factor (anti-VEGF)-based therapy has been crucial in the treatment of neovascular AMD, it is necessary to deepen our understanding of the underlying disease mechanisms to move forward to next-generation therapies for later-stage forms of this multifactorial disease.

Current Situation and Challenges in Vitreous Substitutes.

Vitreo-retinal disorders constitute a significant portion of treatable ocular diseases. These pathologies often require vitreo-retinal surgery and, as a consequence, the use of vitreous substitutes. Nowadays, the vitreous substitutes that are used in clinical practice are mainly divided into gases (air, SF6 , C2 F6 , C3 F8 ) and liquids (perfluorocarbon liquids, silicone oils, and heavy silicone oils). There are specific advantages and drawbacks to each of these, which determine their clinical indications. However, developing the ideal biomaterial for vitreous substitution continues to be one of the most important challenges in ophthalmology, and a multidisciplinary approach is required. In this sense, recent research has focused on the development of biocompatible, biodegradable, and injectable hydrogels (natural, synthetic, and smart), which also act as medium and long-term internal tamponade agents. This comprehensive review aims to cover the main characteristics and indications for use of the extensive range of vitreous substitutes that are currently used in clinical practice, before going on to describe the hydrogels that have been developed recently and which have emerged as promising biomaterials for vitreous substitution.

Pharmacological Advances in the Treatment of Age-related Macular Degeneration.

Age-related macular degeneration is an acquired degenerative disease that is responsible for severe loss of vision in elderly people. There are two types: dry age-related macular degeneration and wet age-related macular degeneration. Its treatment has been improved and tries to be tailored in the future. The aim of this review is to summarize the pharmacological advances in the treatment of age-related macular degeneration. Regarding dry AMD, there is no effective treatment to reduce its progression. However, some molecules such as lampalizumab and eculizumab were under investigation, although they have shown low efficacy. Herein, in an attempt to prevent dry AMD progression, the most important studies suggested increasing the antioxidants intake and quitting the smoke habit. On the other hand, wet AMD has more developed treatment. Nowadays, the gold standard treatment is anti-VEGF injections. However, more effective molecules are currently under investigation. There are different molecules under research for dry AMD and wet AMD. This fact could help us treat our patients with more effective and lasting drugs but more clinical trials and safety studies are required in order to achieve an optimal treatment.

Pharmacokinetics of Intravitreal Anti-VEGF Drugs in Age-Related Macular Degeneration.

Intravitreal administration of anti-vascular endothelial growth factor (VEGF) antibodies has become the standard treatment for Age-Related Macular Degeneration; however, the knowledge of their pharmacokinetics is limited. A comprehensive review of the preclinical and clinical pharmacokinetic data that were obtained in different studies with intravitreal bevacizumab, ranibizumab, and aflibercept has been conducted. Moreover, the factors that can influence the vitreous pharmacokinetics of these drugs, as well as the methods that were used in the studies for analytical determination, have been exposed. These anti-VEGF drugs present different charge and molecular weights, which play an important role in vitreous distribution and elimination. The pharmacokinetic parameters that were collected differ depending on the species that were involved in the studies and on physiological and pathological conditions, such as vitrectomy and lensectomy. Knowledge of the intravitreal pharmacokinetics of the anti-VEGF drugs that were used in clinical practice is of vital importance.

Review of Intraocular Pharmacokinetics of Anti-Infectives Commonly Used in the Treatment of Infectious Endophthalmitis.

Although intravitreal administration of anti-infectives represents the standard treatment for infectious endophthalmitis, the knowledge about their pharmacokinetics is still limited. In this review, we aimed to summarise the factors influencing the pharmacokinetics of the anti-infective agents. We have conducted a comprehensive review of the preclinical pharmacokinetic parameters obtained in different studies of intravitreal injections of anti-infectives performed on animals, mainly rabbits. The two aspects with the biggest influence on pharmacokinetics are the distribution in the vitreous humour and the elimination through the posterior segment. The distribution can be affected by the molecular weight of the drug, the convection flow of the vitreous, the condition of the vitreous humour depending on the age of the patient, the possible interactions between the drug and the components of the vitreous, and the presence of vitrectomy. Meanwhile, the elimination includes the metabolism of the drug, the clearance via the anterior and posterior routes, and the possible inflammation of the eye resulting from the disease. Understanding the pharmacokinetics of the anti-infectives used in clinical practice is essential for a correct application. The information provided in this review could offer guidance for selecting the best therapeutic option according to the characteristics of the drugs.

Ophthalmic Econazole Hydrogels for the Treatment of Fungal Keratitis.

Econazole is a feasible alternative treatment in the management of fungal keratitis. Nevertheless, its low water solubility is considered the main limitation to the incorporation into ophthalmic formulations. In this work, econazole nitrate is solubilized by using cyclodextrins to achieve an optimum therapeutic concentration. Phase solubility diagrams suggest α-cyclodextrin as the most effective cyclodextrin and later the inclusion complex formed with this one was characterized in solution by 1D, 2D-NMR, and molecular modeling. Econazole-α-cyclodextrin inclusion complex was included in 2 types of ocular hydrogels: a natural polysaccharides ion-sensitive hydrogel and a hyaluronic acid hydrogel. Both of them show no ocular irritation in the hen's egg test on chorioallantoic membrane assay and a controlled econazole release over time. Permeability studies suggest that hydrogels do not modify the econazole nitrate permeability through bovine cornea in comparison with an econazole-α-cyclodextrin inclusion complex solution. Finally, ocular biopermanence studies performed using positron emission tomography show these hydrogels present a high retention time on the eye. Results suggest the developed formulations have a high potential as vehicles for the econazole topical ocular administration as fungal keratitis treatment.

Hidrogel oftálmico de cisteamina para el tratamiento de la cistinosis ocular / Cysteamine ophthalmic hydrogel for the treatment of ocular cystinosis

La cistinosis ocular es una enfermedad rara que se caracteriza por el depósito de cristales de cistina a nivel corneal, los cuales dificultan la visión de los pacientes. La cisteamina oral se administra en forma de cisteamina, pero esta no alcanza la córnea debido a la falta de vascularización corneal, por lo que es necesaria la aplicación tópica ocular. El objetivo del presente trabajo es determinar la estabilidad de un hidrogel oftálmico de cisteamina, potencialmente formulable en servicios de farmacia hospitalaria, conservado este bajo diferentes condiciones de almacenamiento durante un periodo de 30 días. Los parámetros físicos y químicos evaluados han sido la osmolalidad, el pH y la concentración de cisteamina, siendo esta última valorada mediante un método de cromatografía líquida de ultra alta presión, empleando un detector de masas en tándem (UPLC-MS/MS). Los ensayos descriptivos se han basado en la medición de la transparencia y los ensayos microbiológicos en la realización de pruebas de esterilidad. Los resultados obtenidos permiten concluir que el hidrogel de cisteamina es estable durante un periodo de 30 días, recomendándose que su conservación sea en nevera (AU)

Ocular cystinosis is a rare disease characterised by the deposit of cystine crystals on the corneal surface, which hinder patients' eyesight. Oral cysteamine is given as cysteamine; however, it does not reach the cornea due to the lack of corneal vascularization making necessary its administration by the topical ocular route. The aim of the present study is to determine the stability of an ophthalmic hydrogel of cysteamine, which can be potentially prepared at hospital pharmacy departments, under different preservation conditions during a follow-up of 30 days. Different physical and chemical parameters were evaluated: osmolality, pH and cysteamine concentration, which has been measured by a method of ultra performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS). Descriptive assays were also performed, such as transparency measurement and microbiological assays in order to verify its sterility. The obtained results allow us to conclude that the cysteamine hydrogel is stable during 30 days, being recommendable its preservation in refrigerated conditions (AU)

[Cysteamine ophthalmic hydrogel for the treatment of ocular cystinosis]. / Hidrogel oftálmico de cisteamina para el tratamiento de la cistinosis ocular.

Ocular cystinosis is a rare disease characterised by the deposit of cystine crystals on the corneal surface, which hinder patients' eyesight. Oral cysteamine is given as cysteamine; however, it does not reach the cornea due to the lack of corneal vascularization making necessary its  administration by the topical ocular route. The aim of the present study is to  determine the stability of an ophthalmic hydrogel of cysteamine, which can be  potentially prepared at hospital pharmacy departments, under different preservation conditions during a follow-up of 30 days. Different physical  and chemical parameters were evaluated: osmolality, pH and  cysteamine concentration, which has been measured by a method of ultra  performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS).  Descriptive assays were also performed, such as transparency measurement and  microbiological assays in order to verify its sterility. The obtained results  allow us to conclude that the cysteamine hydrogel is stable during 30 days,  being recommendable its preservation in refrigerated conditions.

La cistinosis ocular es una enfermedad rara que se caracteriza por el depósito de  cristales de cistina a nivel corneal, los cuales dificultan la visión de  los pacientes. La cisteamina oral se administra en forma de cisteamina, pero  esta no alcanza la córnea debido a la falta de vascularización corneal, por lo que  es necesaria la aplicación tópica ocular. El objetivo del presente trabajo es  determinar la estabilidad de un hidrogel oftálmico de cisteamina, potencialmente  formulable en servicios de farmacia hospitalaria, conservado  este bajo diferentes condiciones de almacenamiento durante un periodo de 30  días. Los parámetros físicos y químicos evaluados han sido la osmolalidad, el pH  y la concentración de cisteamina, siendo esta última valorada mediante un  método de cromatografía líquida de ultra alta presión, empleando un detector de  masas en tándem (UPLC-MS/MS). Los ensayos descriptivos se han basado  en la medición de la transparencia y los ensayos microbiológicos en la realización  de pruebas de esterilidad. Los resultados obtenidos permiten  concluir que el hidrogel de cisteamina es estable durante un periodo de 30 días,  recomendándose que su conservación sea en nevera.

Preclinical PET Study of Intravitreal Injections.

Purpose: This work aimed at describing the time course of vitreous clearance through the use of positron emission tomography (PET) as a noninvasive tool for pharmacokinetic studies of intravitreal injection. Methods: The pharmacokinetic profile of intravitreal injections of molecules labeled with 18Fluorine (18F) was evaluated in adult Sprague Dawley rats by using a dedicated small-animal PET/computed tomography scanner. Different conditions were studied: three molecules radiolabeled with 18F (18F-FDG, 18F-NaF, and 18F-Choline), three volumes of intravitreal injections (7, 4, and 2 µL), and absence or presence of eye inflammation (uveitis). Results: Our results showed that there are significant pharmacokinetic differences among the radiolabeled molecules studied but not among the injected volumes. The presence or absence of uveitis was an important factor in vitreous clearance, since the elimination of the drug was clearly increased when this condition is present. Conclusions: Intravitreal pharmacokinetic studies based on the use of dedicated PET imaging can be of potential interest as noninvasive tools in ophthalmic drug development in small animals.

Cysteamine polysaccharide hydrogels: Study of extended ocular delivery and biopermanence time by PET imaging.

Cystinosis is a rare autosomal recessive disorder in which cystine crystals accumulate within the lysosomes of various organs, including the cornea. Ocular treatment is based on the administration of cysteamine eye drops, requiring its instillation several times per day. We have introduced the cysteamine in two types of previously developed ocular hydrogels (ion sensitive hydrogel with the polymers gellan gum and kappa-carrageenan and another one composed of hyaluronic acid), aiming at increasing the ocular retention in order to extend the dosing interval. The biopermanence studies (direct measurements and PET/CT) show that these formulations present a high retention time on the ocular surface of rats. From the in vitro release study we determined that both hydrogels can control the release of cysteamine over time, showing a zero order kinetics during four hours. At the same time, these hydrogels could act as corneal absorption promoters, as they allow a higher permeation of cysteamine through bovine cornea compared to a solution. HET-CAM test and cytotoxicity assays show no irritation on the ocular surface. These results demonstrate that the developed formulations present a high potential as vehicles for the topical ocular administration of cysteamine.

In Vitro Evaluation of the Ophthalmic Toxicity Profile of Chlorhexidine and Propamidine Isethionate Eye Drops.

PURPOSE: Acanthamoeba keratitis causes frequent epithelial lesions that fully expose the corneal stroma. The aim of this study was to determine the toxic profile of chlorhexidine and propamidine eye drops. METHODS: We used primary human keratocytes in cell culture in combination with a novel technology that evaluates dynamic real-time cytotoxicity through impedance analysis. Additional studies such as a classic cell viability test (WST-1®), a bovine corneal opacity and permeability assay, and an irritation eye study (Hen's Egg Test [HET]) have been made. RESULTS: Both eye drop formulations showed a time- and concentration-dependent toxicity profile, in which long periods and high concentrations were more detrimental to cells. In prolonged times of exposure, propamidine is more harmful to cells than chlorhexidine. On the contrary, no irritation has been detected in using the HET-chorioallantoic membrane test and no alterations in the corneal transparency nor permeability was produced by the treatment with both eye drops. CONCLUSIONS: In culture assay, chlorhexidine eye drops have proven to be less cytotoxic than Brolene® for a long contact period of time, but no signs of irritation or alterations in transparency or permeability have been observed in the cornea after both treatments.

Positron Emission Tomography for the Development and Characterization of Corneal Permanence of Ophthalmic Pharmaceutical Formulations.

Purpose: This work is aimed at describing the utility of positron emission tomography/computed tomography (PET/CT) as a noninvasive tool for pharmacokinetic studies of biopermanence of topical ocular formulations. Methods: The corneal biopermanence of a topical ophthalmic formulation containing gellan gum and kappa carragenan (0.82% wt/vol) labeled with 18Fluorine (18F) radiotracers (18F-FDG and 18F-NaF) was evaluated by using a dedicated small-animal PET/CT, and compared with the biopermanence of an aqueous solution labeled with the same compounds. Regions of interest (ROIs) were manually drawn on the reconstructed PET images for quantifying the radioactivity concentration in the eye. The biopermanence of the formulations was determined by measuring the radioactivity concentration at different times after topical application. Additionally, cellular and ex vivo safety assays were performed to assess the safety of the performed procedures. Results: Differences were observed in the ocular pharmacokinetics of the two formulations. After 1.5 hours of contact, 90% of the hydrogel remained in the ocular surface, while only 69% of the control solution remained. Furthermore, it was observed that flickering had a very important role in the approach of the trial. The application of 18F-FDG in the eye was neither irritating nor cytotoxic for human corneal epithelial cells. Conclusions: The use of small-animal PET and 18F radiotracers in ocular pharmacokinetics of ophthalmic formulations is feasible and could be a safe method for future ocular pharmacokinetic studies in humans.

In vivo eye surface residence determination by high-resolution scintigraphy of a novel ion-sensitive hydrogel based on gellan gum and kappa-carrageenan.

In last years, sensitive hydrogels have become a breakthrough in ophthalmic pharmaceutical technology aimed at developing new strategies to increase the residence time of active substances. In a previous paper, we qualitatively demonstrated the capacity of a new ion sensitive hydrogel to increase the residence time. Nevertheless, the clearance of the gel from the ocular surface was not quantifiable with the used methodology. The aim of the present work was to use a well-established approach based on scintigraphy to quantitatively estimate the residence time of the previously proposed hydrogel. The rat corneal residence time of a topic ophthalmic formulation containing gellan gum and kappa carragenan (0.82% w/v) labeled with 99mTc-DTPA radiotracer was evaluated and compared with the residence of an aqueous solution. Ophthalmic safety studies such as eye irritation or passage through the cornea were also carried out. After 1.5h of contact, 77% of the hydrogel remained in the ocular surface, presenting kinetics of disappearance one-phase decay and a half time of 262min. We conclude that the novel ophthalmic hydrogel developed with kappa carrageenan and gellan gum remains for long periods of time on the corneal surface, presenting a drop that fits an exponential decay.

Evaluation of the in vitro ocular toxicity of the fortified antibiotic eye drops prepared at the Hospital Pharmacy Departments / Evaluación de la toxicidad ocular in vitro de los colirios fortificados antibióticos elaborados en los Servicios de Farmacia Hospitalaria

The use of parenteral antibiotic eye drop formulations with non-marketed compositions or concentrations, commonly called fortified antibiotic eye drops, is a common practice in Ophthalmology in the hospital setting. The aim of this study was to evaluate the in vitro ocular toxicity of the main fortified antibiotic eye drops prepared in the Hospital Pharmacy Departments. We have conducted an in vitro experimental study in order to test the toxicity of gentamicin, amikacin, cefazolin, ceftazidime, vancomycin, colistimethate sodium and imipenem-cilastatin eye drops; their cytotoxicity and acute tissue irritation have been evaluated. Cell-based assays were performed on human stromal keratocytes, using a cell-based impedance biosensor system [xCELLigence Real-Time System Cell Analyzer (RTCA)], and the Hen’s Egg Test for the ocular irritation tests. All the eye drops, except for vancomycin and imipenem, have shown a cytotoxic effect dependent on concentration and time; higher concentrations and longer exposure times will cause a steeper decline in the population of stromal keratocytes. Vancomycin showed a major initial cytotoxic effect, which was reverted over time; and imipenem appeared as a non-toxic compound for stromal cells. The eye drops with the highest irritating effect on the ocular surface were gentamicin and vancomycin. Those antibiotic eye drops prepared at the Hospital Pharmacy Departments included in this study were considered as compounds potentially cytotoxic for the ocular surface; this toxicity was dependent on the concentration used (AU)

El uso de reformulaciones de antibióticos parenterales en forma de colirios de composición o concentraciones no comercializadas, comúnmente denominados colirios antibióticos reforzados, es una práctica habitual en oftalmología a nivel hospitalario. El objetivo del presente trabajo ha consistido en evaluar la toxicidad ocular in vitro de los principales colirios antibióticos reforzados elaborados en los Servicios de Farmacia Hospitalaria. Hemos realizado un estudio experimental in vitro para evaluar la toxicidad de los colirios de gentamicina, amikacina, cefazolina, ceftazidima, vancomicina, colistimetato de sodio e imipenem-cilastatina en el que se ha evaluado su citotoxicidad y la irritación tisular aguda. Los ensayos celulares se realizan sobre queratocitos estromales humanos, mediante la utilización de un sistema biosensor de impedancia celular [(xCELLigence Real-Time System Cell Analyzer (RTCA)] y los ensayos de irritación ocular mediante el ensayo Hen´s Egg Test. Todos los colirios, excepto vancomicina e imipenem, han mostrado un efecto citotóxico de concentración y tiempo dependiente, siendo las concentraciones más altas y los tiempos más prolongados los que provocan un descenso más pronunciado en la población de queratocitos estromales. La vancomicina muestra un importante efecto citotóxico inicial que revierte con el transcurso del tiempo y el imipenem se muestra como un compuesto no tóxico para las células estromales. Los compuestos con mayor efecto irritante para la superficie ocular son la gentamicina y la vancomicina. Los colirios antiinfecciosos elaborados en los Servicios de Farmacia Hospitalaria estudiados se muestran como compuestos potencialmente citotóxicos para la superficie ocular, siendo esta toxicidad dependiente de la concentración utilizada (AU)

Evaluation of the in vitro ocular toxicity of the fortified antibiotic eye drops prepared at the Hospital Pharmacy Departments.

The use of parenteral antibiotic eye drop formulations with non-marketed compositions or concentrations, commonly called fortified antibiotic eye drops, is a common practice in Ophthalmology in the hospital setting. The aim of this study was to evaluate the in vitro ocular toxicity of the main fortified antibiotic eye drops prepared in the Hospital Pharmacy Departments. We have conducted an in vitro experimental study in order to test the toxicity of gentamicin, amikacin, cefazolin, ceftazidime, vancomycin, colistimethate sodium and imipenem-cilastatin eye drops; their cytotoxicity and acute tissue irritation have been evaluated. Cell-based assays were performed on human stromal keratocytes, using a cell-based impedance biosensor system [xCELLigence Real-Time System Cell Analyzer (RTCA)], and the Hen's Egg Test for the ocular irritation tests. All the eye drops, except for vancomycin and imipenem, have shown a cytotoxic effect dependent on concentration and time; higher concentrations and longer exposure times will cause a steeper decline in the population of stromal keratocytes. Vancomycin showed a major initial cytotoxic effect, which was reverted over time; and imipenem appeared as a non-toxic compound for stromal cells. The eye drops with the highest irritating effect on the ocular surface were gentamicin and vancomycin. Those antibiotic eye drops prepared at the Hospital Pharmacy Departments included in this study were considered as compounds potentially cytotoxic for the ocular surface; this toxicity was dependent on the concentration used.

El uso de reformulaciones de antibioticos parenterales en forma de colirios de composicion o concentraciones no comercializadas, comunmente denominados colirios antibioticos reforzados, es una practica habitual en oftalmologia a nivel hospitalario. El objetivo del presente trabajo ha consistido en evaluar la toxicidad ocular in vitro de los principales colirios antibioticos reforzados elaborados en los Servicios de Farmacia Hospitalaria. Hemos realizado un estudio experimental in vitro para evaluar la toxicidad de los colirios de gentamicina, amikacina, cefazolina, ceftazidima, vancomicina, colistimetato de sodio e imipenem- cilastatina en el que se ha evaluado su citotoxicidad y la irritacion tisular aguda. Los ensayos celulares se realizan sobre queratocitos estromales humanos, mediante la utilizacion de un sistema biosensor de impedancia celular [(xCELLigence Real- Time System Cell Analyzer (RTCA)] y los ensayos de irritacion ocular mediante el ensayo Hen/s Egg Test. Todos los colirios, excepto vancomicina e imipenem, han mostrado un efecto citotoxico de concentracion y tiempo dependiente, siendo las concentraciones mas altas y los tiempos mas prolongados los que provocan un descenso mas pronunciado en la poblacion de queratocitos estromales. La vancomicina muestra un importante efecto citotoxico inicial que revierte con el transcurso del tiempo y el imipenem se muestra como un compuesto no toxico para las celulas estromales. Los compuestos con mayor efecto irritante para la superficie ocular son la gentamicina y la vancomicina. Los colirios antiinfecciosos elaborados en los Servicios de Farmacia Hospitalaria estudiados se muestran como compuestos potencialmente citotoxicos para la superficie ocular, siendo esta toxicidad dependiente de la concentracion utilizada.

TRANSCLERAL DRAINAGE OF SUBRETINAL FLUID, ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR, AND WIDE-FIELD IMAGING-GUIDED LASER IN COATS EXUDATIVE RETINAL DETACHMENT.

PURPOSE: To evaluate the safety and efficacy of combined transscleral drainage of subretinal fluid (SRF) with intravitreal bevacizumab and laser photocoagulation in the management of advanced Coats disease (Stage 3) with exudative retinal detachment. DESIGN: Retrospective interventional case series. METHODS: Retrospective case review of eight eyes in eight children with advanced Coats disease manifested as total or subtotal retinal detachment. All eyes initially underwent surgical drainage of exudative SRF followed by intravitreal injection of bevacizumab and laser photocoagulation. Patients were subsequently followed up for up to 60 months. RESULTS: In all eyes, after SRF drainage and administration of one to two intravitreal injections, SRF was completely eliminated. Patients required up to four sessions of laser photocoagulation. Retinal detachment consequently reduced with all patients showing total retinal reattachment and resolution of the subretinal exudates. At the last follow-up, no patient showed recurrent SRF and no ocular complications related to bevacizumab nor evidence of further disease progression were noted. CONCLUSION: The authors present a new therapeutic approach that allows for the first time successful treatment of advanced cases of exudative retinal detachment in Coats disease without the need for vitrectomy. Transscleral drainage of SRF accompanied by anti-vascular endothelial growth factor injection and laser photocoagulation appears to be successful in halting progression of advanced Coats disease with exudative detachment and a less invasive approach when compared with conventional management.

Ocular safety comparison of non-steroidal anti-inflammatory eye drops used in pseudophakic cystoid macular edema prevention.

Non-steroidal anti-inflammatory drug (NSAID) eye drops are widely used to treat ocular inflammatory conditions related to ophthalmic surgical procedures, such as pseudophakic cystoid macular edema, and they have been used for off-label treatments. The most commonly used NSAIDs are diclofenac and ketorolac and the new molecules bromfenac and nepafenac have also been used. We used primary human keratocytes in cell culture in combination with a novel technology that evaluates dynamic real-time cytotoxicity through impedance analysis. This study also included classic cell viability tests (WST-1(®) and AlamarBlue(®)), wound healing assay, Hen's Egg Test and an ex vivo histopathological assay. NSAIDs were shown to have important cytotoxicities and to retard the healing response. Furthermore, the new eye drops containing bromfenac and nepafenac were more cytotoxic than the more classical eye drops. Nevertheless, no immuno-histochemical changes or acute irritation processes were observed after the administration of any eye drops tested. Due to cytotoxicity and the total absence of discomfort and observable injuries after the administration of these drugs, significant corneal alterations, such as corneal melts, can develop without any previous warning signs of toxicity.