Glaucoma drainage devices in children: an updated review.

Implantation of glaucoma drainage devices is a valuable therapeutic option, particularly in children with glaucoma refractory to primary surgical treatment. Glaucoma drainage devices are typically used when conjunctival scarring hampers filtration surgery or prior angle procedures are not effective in controlling intraocular pressure. Despite known complications, the use of glaucoma drainage devices in children has increased in recent years, even as the primary surgical option. In this review, we evaluate the results of recent studies involving the implantation of glaucoma drainage devices in children, discussing new advances, and comparing the success rates and complications of different devices.

Bilateral Peters' anomaly, aniridia and Wilms tumour (WAGR syndrome) in monozygotic twins.

AIM: This study reports the bilateral association of Peters' anomaly and congenital aniridia in monozygotic twins subsequently diagnosed with Wilms tumour (WAGR syndrome). METHODS: Two monozygotic female twins were referred at age 2 months with bilateral corneal opacity. A diagnosis of Peters' anomaly associated to aniridia was made in both eyes of both twins. Physical examination and ultrasonography were carried out at 12 months of age to explore the possibility of WAGR-related anomalies, specifically Wilms tumour. DNA were isolated and subjected to whole exome sequencing. RESULTS: Peters' anomaly associated to aniridia in both eyes as well as bilateral Wilms tumour in both children were diagnosed. Exome analyses showed a large heterozygous deletion encompassing 6 648 473 bp in chromosome 11p13, using Integrative Genomics Viewer and AnnotSV software. CONCLUSION: WAGR syndrome is a rare contiguous gene deletion syndrome with a greater risk of developing Wilms tumour associated with Peters' anomaly and congenital aniridia. However, co-occurrence of both anomalies was rarely reported in twins, and never in both eyes of monozygotic twins. Here, we report the bilateral association of Peters' anomaly and congenital aniridia in monozygotic twins with WAGR syndrome.

Bilateral acute iris transillumination (BAIT) syndrome: Differential diagnosis based on clinical, OCT and UBM findings.

INTRODUCTION: Bilateral acute iris transillumination (BAIT) is a relatively new syndrome whose etiopathogenesis is still not fully understood. It is characterized by acute bilateral onset of intense pigment dispersion in the anterior chamber, iris depigmentation with severe transillumination defects, accentuated pigment deposition in the angle, and elevated intraocular pressure (IOP). In literature, the first case was of bilateral acute iris depigmentation (BADI) reported in 2004 in a 77-year-old woman. In 2019, Perone et al. published a review about BAIT syndrome. They reported a total of 79 cases have been published up that date, mainly in Europe and especially in Turkey and Belgium. The majority of reported cases were of bilateral acute iris depigmentation (BADI). BAIT syndrome might be mainly confused with acute iridocyclitis, acute primary angle-closure (APAC) and pigment dispersion syndrome (PDS). In relation to BAIT, controversies still exist regarding the etiology being the differential diagnosis of paramount importance for adequate treatment. PURPOSE: To report a case of BAIT syndrome associated to refractory glaucoma and to discuss the differential diagnosis based on clinical, OCT and UBM findings. METHODS: We present a case of BAIT syndrome in which clinical, OCT and UBM findings have pointed out the similarities and, mainly the diagnosis differences with other ocular diseases. CONCLUSIONS: BAIT syndrome with accentuated IOP rise must be differentiated of other ocular diseases. It requires urgent clinical therapy and/or surgical management as occurred in the present case for avoiding structural damage in OCT and visual field loss. OCT and UBM are critical for early recognition, differential diagnosis and management.

Influence of unilateral eyelid spasms and botulinum toxin treatment on intraocular pressure measured by transpalpebral tonometer.

PURPOSE: Eyelid spasms might be associated with elevated intraocular pressure (IOP) in hemifacial spasm (HFS) patients. IOP assessment using a Goldmann applanation tonometer (GAT) is often compromised by eyelid spasms. This study aimed to assess the effect of HFS on IOP measurements using the transpalpebral tonometer Diaton® before and after treatment with botulinum toxin type A (BTX-A) and compared Diaton® and GAT measurements after treatment with BTX-A. METHODS: IOP measurements were obtained with Diaton® in 27 patients with moderate-to-severe HFS before and after treatment with BTX-A. After treatment, the IOP was also measured using GAT and the results were compared with the ones measured with a Diaton®. The patients underwent automated perimetry, OCT, and pachymetry for screening to glaucoma. RESULTS: Mean IOP with Diaton® was 11 ± 3.42 mmHg before treatment in the affected eye and 9 ± 2.98 mmHg in the contralateral eye. This difference was statistically significant (P = 0.012). However, after treatment with BTX-A, no interocular difference was found in IOP obtained with Diaton® (P = 0.204) or GAT (P = 0.971). Comparison between GAT and Diaton® measurements showed no significant differences after BTX-A treatment between the affected (P = 0.212) and contralateral eye (P = 0.971). CONCLUSIONS: A significant reduction in IOP measurements on the affected side of HFS patients was observed after treatment with BTX-A, demonstrating that eyelid spasms may increase the IOP. No significant difference was observed between Diaton® and GAT measurements after the application of BTX-A. No differences were found in automated perimetry, OCT, and CCT when comparing affected eyes with contralateral eyes.

Traboulsi syndrome without features of Marfan syndrome caused by a novel homozygous ASPH variant associated with a heterozygous FBN1 variant.

BACKGROUND: Traboulsi syndrome is a rare disease clinically characterized by facial dysmorphism, abnormal spontaneous filtering blebs, ectopia lentis (EL) and multiple anterior segment abnormalities. MATERIAL AND METHODS: An 18-year-old female was referred to the Emergency Service of Hospital São Geraldo (HSG) claiming decreased right eye (RE) visual acuity associated with ocular pain that was noticed approximately 2 months earlier. She underwent a complete ophthalmic and physical examination including hands, ankle, wrist and chest X-ray, abdominal ultrasound, echocardiogram and genetic analysis (whole-exome sequencing). RESULTS: The ophthalmic examination revealed a high myopia with spherical equivalent of - 9.50 D and best corrected visual acuity (BCVA) of 20/60 in RE and - 9.25 D with BCVA of 20/30 in the left eye (LE). Slit-lamp examination showed normal conjunctiva in both eyes (BE) and a superior-temporal cystic lesion in RE and nasal in LE; the flat anterior chamber in BE with the transparent crystalline lens touches the central corneal endothelium in the RE. Fundoscopy suggested glaucoma as the cup/disc ratio was 0.7, although the intraocular pressure (IOP) was 10 mmHg in BE without medication. Validation of data from whole exome demonstrated a novel splicing homozygous pathogenic variant (PV) (c.1765-1G>A) of the ASPH gene as well as a heterozygous variant of unknown significance (VUS) of the FBN1 gene (c.6832C>T). CONCLUSION: We here report a novel splice-affecting homozygous pathogenic variant in the ASPH gene that was detected in a Brazilian patient with clinical features of Traboulsi syndrome.

Outcomes of early versus delayed trabeculotomy for primary congenital glaucoma.

PURPOSE: In patients with primary congenital glaucoma (PCG), elevated intraocular pressure (IOP) causes abnormal eye growth. This study compared the outcomes of children with PCG who underwent ab externo trabeculotomy (TROC) at age ≤ 6 months (early TROC) and of those who underwent TROC at age > 6 months (delayed TROC). METHODS: Intraocular pressure, horizontal corneal diameter (HCD), central corneal thickness (CCT) and axial length (AL) were compared before TROC and at 1-, 3-, 6- and 12-month follow-up visits between the groups of children who underwent TROC until or after 6 months of age. The ALs of these groups were also compared with the ALs of healthy age-matched eyes examined under the same conditions. RESULTS: Trabeculotomy was performed in 43 children: 18 (33 eyes) aged 6 months (group 1) and 25 (37 eyes) aged >6 months (group 2); the mean ages were 86.56 ± 53.64 and 504.48 ± 448.14 days, respectively. The mean pre- and 12-month postoperative IOP values were 15.97 ± 4.78/16.62 ± 4.85 and 9.77 ± 2.88/10.93 ± 4.83 mmHg, respectively. Delayed TROC was associated with abnormal AL in 31 (88.6%) out of 37 eyes, while after early TROC, only 13 (41.9%) out of 33 eyes had abnormal AL (chi-square, 8.00; p = 0.03). In multivariable analysis, each 1-mmHg increase in preoperative IOP was associated with a 0.25-mmHg increase at 12 months (p = 0.04). On average, the mean IOP of the delayed TROC group was higher than that of the early TROC group by 3.72 mmHg at postoperative month 12 (95% CI = 0.44-6.99; p = 0.02). CONCLUSION: Compared with delayed TROC, early TROC is associated with reduced IOP and substantially reduced incidence of abnormal AL at postoperative month 12.

Twenty-four hours intraocular pressure in keratoconic eyes assessed by applanation tonometry and Tono-Pen AVIA.

AIM: To assess intraocular pressure (IOP) during the daily curve of intraocular pressure (DCPo) in keratoconic eyes and compare Goldmann applanation tonometer (GAT), without and with astigmatism correction (nGAT and cGAT) and Tono-Pen AVIA (TPA) assessment methods. METHODS: Thirty-nine keratoconic eyes of 24 patients were assessed. DCPo was evaluated with five IOP measurements; four were performed with a GAT (nGAT and cGAT), and a Tono-Pen AVIA (TPA) at various times throughout the day. RESULTS: Mean IOP DCPo values (mm Hg) were: nGAT, 9.9±2.6; cGAT, 11.3±2.6; TPA 12.3±3.1. Mean IOP DCPo differences (mm Hg) and Spearman's correlation coefficients were as follows: cGATc-nGAT, 1.32±1.31, r s=0.879 (P<0.01); cGAT-TPA, -1.02±2.08, r s=0.723 (P<0.01); and nGAT-TPA, -2.35±2.23, r s=0.730 (P<0.01). Bland-Altman analysis for agreement between cGAT-TPA and nGAT-TPA mean IOP DCPo measurements revealed a mean difference of 1.02 (95%CI, 0.35-1.70) and 2.35 (95%CI, 1.62-3.07) mm Hg, respectively. Regression analysis yielded the following equation: TPA IOP=5.49+0.775×cGAT-0.015×ACD-0.299×corneal astig matism, which allowed us to infer TPA IOP values from other parameters. CONCLUSION: In keratoconic eyes, IOP peaks of DCPo measurements are identified at 6 a.m., independent of the tonometer. The mean DCPo values are: TPA>cGAT>nGAT. IOP TPA measures are predictive of cGAT values, adjusted according to anterior chamber depth and corneal astigmatism.

Glaucoma drainage devices / Dispositivos de drenagem para glaucoma

ABSTRACT Glaucoma drainage devices are important therapeutic options for cases of refractory glaucoma, in which trabeculectomy with antimetabolites has shown high risk of failure. There are devices with different sizes, designs and materials, and several studies have been conducted to test their safety and effectiveness. Despite known complications, their use has progressively increased in recent years, and they are the primary surgical option, in some situations. The aim of this review is to discuss the importance, mechanisms, biomaterials, results and complications of glaucoma drainage devices.

RESUMO Os dispositivos de drenagem para glaucoma são importante opção terapêutica em casos de glaucomas refratários, nos quais a trabeculectomia com antimetabólitos tem alta chance de falência. Há dispositivos com diferentes tamanhos, desenhos e materiais, e muitos estudos foram realizados para testar sua segurança e eficácia. Apesar de suas conhecidas complicações, seu uso tem aumentado progressivamente nos últimos anos, inclusive como primeira opção cirúrgica, em algumas situações. O objetivo desta revisão foi discutir a importância, os mecanismos, os biomateriais, os resultados e as complicações dos dispositivos de drenagem para glaucoma.

SD-OCT assessment and visual field changes 1 year or more after a single episode of unilateral acute primary angle closure / Avaliação do SD-OCT e mudanças do campo visual 1 ano ou mais após episódio único de fechamento angular primário agudo unilateral

ABSTRACT Objective: To evaluate structural and visual field (VF) changes after ≥1 year of a single acute primary angle closure (APAC) attack using spectral-domain optical coherence tomography (SD-OCT) and standard automated perimetry (SAP). Methods: Patients with a single unilateral APAC crisis at least 1 year ago were included consecutively from 2013 to 2016. Contralateral eye was used as control. All patients underwent ophthalmic examination, RNFL imaging by SD-OCT, and SAP using Octopus 1-2-3. Results: 54 eyes (27 patients) were enrolled. Male-to-female ratio was 1:2. Mean time for the SD-OCT and SAP assessment after the crisis was 5.0±5.1 (1.0-23.5) years, and IOP was 52.5±9.8 mmHg. In APAC eyes, the thicknesses of all quadrants of peripapillary RNFL (36.3%; P<0.001) and some macular sections (from 2.1% to 4.7%; P<0.01) were reduced compared to contralateral eyes. Additionally, in APAC eyes, the mean defect on VF was negatively and statistically correlated with the reduction of all quadrants of peripapillary RNFL thickness. Conclusion: A single episode of APAC was associated with peripapillary RNFL and macular thickness and with VF defects after ≥1 year of the crisis in the affected eye. Statistically meaningful correlations were found between structural and functional damage.

RESUMO Objetivo: Avaliar alterações estruturais e do campo visual 1 ano ou mais após uma crise única de fechamento angular primário agudo utilizando tomografia de coerência óptica de domínio espectral e perimetria automatizada padronizada. Métodos: Pacientes que apresentaram crise unilateral única de fechamento angular primário agudo há pelo menos 1 ano foram consecutivamente incluídos entre 2013 e 2016. Os olhos contralaterais foram utilizados como controles. Todos os pacientes foram submetidos a exame oftalmológico, avaliação das camadas de fibras nervosas da retina utilizando tomografia de coerência óptica de domínio espectral e perimetria automatizada padronizada com o Octopus 1-2-3. Resultados: Foram incluídos 54 olhos (27 pacientes) com razão homem:mulher de 1:2. O tempo médio após a crise foi de 5,0±5,1 anos (1,0 a 23,5) e a pressão intraocular na crise foi 52,5±9,8mmHg. Nos olhos com fechamento angular primário agudo, todas as espessuras das camadas de fibras nervosas da retina peripapilares (36,3%; p<0,001) e de algumas seções maculares (de 2,1 a 4,7%; p<0,01) estavam reduzidas em comparação aos olhos contralaterais. Além do mais, nos olhos submetidos a fechamento angular primário agudo, o mean defect do campo visual foi estatisticamente e negativamente correlacionado com a redução da espessura de todos os quadrantes peripapilares da camada de fibras nervosas da retina. Conclusão: Um único episódio de fechamento angular primário agudo foi associado com redução na espessura da camada de fibras nervosas da retina peripapilar e da espessura macular e com defeitos de campo visual 1 ano ou mais após a crise no olho afetado. Correlações estatisticamente significativas foram identificadas entre danos estruturais e funcionais.

Use of machine learning to predict the risk of early morning intraocular pressure peaks in glaucoma patients and suspects / Uso de aprendizado de máquina para predizer o risco de picos de pressão intraocular no início da manhã em pacientes com glaucoma e suspeitos

ABSTRACT Purpose: To use machine learning to predict the risk of intraocular pressure peaks at 6 a.m. in primary open-angle glaucoma patients and suspects. Methods: This cross-sectional observational study included 98 eyes of 98 patients who underwent a 24-hour intraocular pressure curve (including the intraocular pressure measurements at 6 a.m.). The diurnal intraocular pressure curve was defined as a series of three measurements at 8 a.m., 9 a.m., and 11 a.m. from the 24-hour intraocular pressure curve. Two new variables were introduced: slope and concavity. The slope of the curve was calculated as the difference between intraocular pressure measurements at 9 a.m. and 8 a.m. and reflected the intraocular pressure change in the first hour. The concavity of the curve was calculated as the difference between the slopes at 9 a.m. and 8 a.m. and indicated if the curve was bent upward or downward. A classification tree was used to determine a multivariate algorithm from the measurements of the diurnal intraocular pressure curve to predict the risk of elevated intraocular pressure at 6 a.m. Results: Forty-nine (50%) eyes had intraocular pressure measurements at 6 a.m. >21 mmHg, and the median intraocular pressure peak in these eyes at 6 a.m. was 26 mmHg. The best predictors of intraocular pressure measurements >21 mmHg at 6 a.m. were the intraocular pressure measurements at 8 a.m. and concavity. The proposed model achieved a sensitivity of 100% and a specificity of 86%, resulting in an accuracy of 93%. Conclusions: The machine learning approach was able to predict the risk of intraocular pressure peaks at 6 a.m. with good accuracy. This new approach to the diurnal intraocular pressure curve may become a widely used tool in daily practice and the indication of a 24-hour intraocular pressure curve could be rationalized according to risk stratification.

RESUMO Objetivo: Utilizar aprendizado de máquina para predizer o risco de picos de pressão intraocular às 6 AM em pacientes com glaucoma primário de ângulo aberto e suspeitos. Métodos: Esse estudo observacional transversal incluiu 98 olhos de 98 pacientes submetidos à curva de 24 horas de pressão intraocular (incluindo as medidas às 6 AM). A curva diurna de pressão intraocular foi definida como uma série de três medidas da curva de 24 horas de pressão intraocular às 8 AM, às 9 AM e às 11 AM. Duas novas variáveis foram apresentadas: inclinação e concavidade. A inclinação da curva às 8 AM foi calculada como a diferença entre pressão intraocular às 9 AM e 8 AM e reflete a variação da pressão intraocular na primeira hora. A concavidade da curva foi calculada como a diferença entre as inclinações às 9 AM e às 8 AM e pode ser para cima ou para baixo. Uma árvore de classificação foi usada para determinar um algoritmo multivariado a partir das medidas da curva diurna para prever o risco de pressão intraocular elevada às 6 AM. Resultados: Quarenta e nove (50%) olhos apresentaram pressão intraocular às 6 AM >21 mmHg e a mediana do pico de pressão intraocularPIO foi 26 mmHg. Os melhores preditores de pressão intraocular às 6 AM >21 mmHg foram a pressão intraocular às 8 AM e a concavidade. O modelo proposto apresentou uma sensibilidade de 100% e uma especificidade de 86%, com uma acurácia de 93%. Conclusões: A abordagem de aprendizado de máquina foi capaz de prever o risco de picos de pressão intraocular às 6 AM com uma boa acurácia. Essa nova abordagem para a curva diurna de pressão intraocular pode se tornar uma ferramenta amplamente utilizada na prática clínica e a indicação da curva de 24 horas de pressão intraocular pode ser racionalizada de acordo com a estratificação de risco.

Use of machine learning to predict the risk of early morning intraocular pressure peaks in glaucoma patients and suspects.

PURPOSE: To use machine learning to predict the risk of intraocular pressure peaks at 6 a.m. in primary open-angle glaucoma patients and suspects. METHODS: This cross-sectional observational study included 98 eyes of 98 patients who underwent a 24-hour intraocular pressure curve (including the intraocular pressure measurements at 6 a.m.). The diurnal intraocular pressure curve was defined as a series of three measurements at 8 a.m., 9 a.m., and 11 a.m. from the 24-hour intraocular pressure curve. Two new variables were introduced: slope and concavity. The slope of the curve was calculated as the difference between intraocular pressure measurements at 9 a.m. and 8 a.m. and reflected the intraocular pressure change in the first hour. The concavity of the curve was calculated as the difference between the slopes at 9 a.m. and 8 a.m. and indicated if the curve was bent upward or downward. A classification tree was used to determine a multivariate algorithm from the measurements of the diurnal intraocular pressure curve to predict the risk of elevated intraocular pressure at 6 a.m. RESULTS: Forty-nine (50%) eyes had intraocular pressure measurements at 6 a.m. >21 mmHg, and the median intraocular pressure peak in these eyes at 6 a.m. was 26 mmHg. The best predictors of intraocular pressure measurements >21 mmHg at 6 a.m. were the intraocular pressure measurements at 8 a.m. and concavity. The proposed model achieved a sensitivity of 100% and a specificity of 86%, resulting in an accuracy of 93%. CONCLUSIONS: The machine learning approach was able to predict the risk of intraocular pressure peaks at 6 a.m. with good accuracy. This new approach to the diurnal intraocular pressure curve may become a widely used tool in daily practice and the indication of a 24-hour intraocular pressure curve could be rationalized according to risk stratification.

Comparison of Tono-Pen Avia and Handheld Applanation Tonometry in Primary Congenital Glaucoma.

PRCIS: Tono-Pen AVIA (TPA) intraocular pressure (IOP) values are different from those taken with handheld Goldmann applanation tonometer (GAT) in primary congenital glaucoma (PCG). These differences indicate both tonometers cannot be used interchangeably for measuring IOP in PCG. PURPOSE: The aim was to compare IOP measurements obtained using TPA and a handheld version of GAT in children with PCG. MATERIALS AND METHODS: Forty-two eyes from 23 patients were evaluated for central corneal thickness (CCT), axial length, biomicroscopy and IOP measurement with TPA and a handheld GAT under inhalation anesthesia. After 1 eye from each patient was randomized, paired the Student t-test and the Pearson correlation were used for analysis. Generalized linear mixed model was used to estimate the difference between tonometers. RESULTS: Mean age of children was 28.3±20.5 months. Mean axial length was 24.89±3.33 mm and mean CCT was 605.9±81.0 µm. Mean IOP was 22.1±9.6 for TPA and 14.0±4.5 mm Hg for GAT. There was a significant difference of 8.1±6.9 mm Hg between TPA IOP and GAT IOP (P<0.001). Each 6 months increase in age was associated with 1.32 mm Hg reduction in the difference between tonometers (P=0.002) and each 1 mm Hg higher of mean GAT IOP was associated with -0.73 mm Hg in the difference between TPA and GAT (P=0.002). Also, for every 20 µm increase in CCT an increase of 1.16 mm Hg in the difference between both devices was expected (P=0.003), after adjustment for potentially confounding variables. CONCLUSION: There is a significant difference between TPA IOP and GAT IOP in PCG. The difference between TPA and GAT in PCG is influenced by CCT, age and GAT IOP value.

Topical Bimatoprost Insert for Primary Open-Angle Glaucoma and Ocular Hypertension Treatment - A Phase II Controlled Study.

INTRODUCTION: The most common treatment for Primary Open-Angle Glaucoma (POAG) is the daily use of eye drops. Sustained-release drug delivery systems have been developed to improve patient adherence by achieving prolonged therapeutic drug concentrations in ocular target tissues while limiting systemic exposure. The purpose of this study is to compare the efficacy and safety of bimatoprost inserts with bimatoprost eye drops in patients with POAG and Ocular Hypertension (OH). METHODS: We include OH and POAG patients aged between 40 and 75 years-old. Both OH and POAG patients had intraocular pressure (IOP) greater than 21 and ≤30 mmHg at 9:00 am without glaucoma medication and normal biomicroscopy. Five normal patients with IOP≤14 mmHg constitute the control group. A chitosan-based insert of bimatoprost was placed at the upper conjunctival fornix of the right eye. In the left eye, patients used one drop of LumiganTM daily at 10:00 pm. For statistical analysis, a two-way analysis of variance (ANOVA), Student t-test, and paired t-test is used. RESULTS: Sixteen POAG and 13 OH patients with a mean age of 61 years were assessed. In both eyes, IOP reduction was similar during three weeks of follow-up (19.5±2.2 mmHg and 16.9±3.1 mmHg), insert, and eye drop, respectively; P=0.165). The percentage of IOP reduction in the third week was 30% for insert and 35% for eye drops (P=0.165). No intolerance or discomfort with the insert was reported. Among the research participants, 58% preferred the use of the insert while 25% preferred eye drops, and 17% reported no preference. CONCLUSION: Bimatoprost-loaded inserts showed similar efficacy to daily bimatoprost eye drops during three weeks of follow up, without major side effects. This might suggest a possible change in the daily therapeutic regimen for the treatment of POAG and OH.

New antiglaucomatous agent for the treatment of open angle glaucoma: Polymeric inserts for drug release and in vitro and in vivo study.

A benzamidine derivative from diminazene was tested for a novel activity: treatment of primary open-angle glaucoma. This drug was incorporated into mucoadhesive polymeric inserts prepared using chitosan (Chs) and chondroitin sulfate (CS). Of current interest is the mucoadhesion, which increases the contact time with the ocular surface, resulting in improved bioavailability; also, the inserts are made to act as a prolonged release system. In the present work the inserts were prepared by the solvent casting method using different polymeric proportions (30:70, 50:50, 75:25% w/w Chs:CS and 100% Chs). Thermal analysis and infrared spectroscopy both demonstrated physical dispersion of the active drug. The most promising was the 50:50% Chs:CS which demonstrated that it was not fragile and has an in vitro release profile of up to 180 minutes. In addition, it presented greater adhesion strength in relation to the other formulations. These physicochemical results corroborate the in vivo tests performed. In this sense, we also demonstrated that the treatment with the 50:50% insert can control the intraocular pressure (IOP) for at least 3 weeks and prevents damage to the retinal ganglion cells (RGCs) compared to the placebo insert. Thus, this indicates thus that the new drug is quite viable and promising in glaucoma treatment.

Correlation between retinal nerve fiber layer thickness and IOP variation in glaucoma suspects and patients with primary open-angle glaucoma.

PURPOSE: To analyze the relationship between retinal nerve fiber layer thickness (RNFLT) and intraocular pressure (IOP) variation in glaucoma suspects (GS) and patients with primary open-angle glaucoma (POAG). METHODS: Thirty-one GS and 34 POAG patients underwent ophthalmologic examination and 24-h IOP measurements. GS had IOPs ranging from 19 to 24 mmHg and/or suspicious appearance of the optic nerve. POAG patients had reproducible abnormal visual fields. We only included patients who presented with short-term IOP fluctuation >6 mm Hg (∆IOP). Only one eye per patient was included through a randomized process. Peripapillary RNFLT was assessed by spectral-domain optical coherence tomography. We correlated RNFLT with IOP parameters. RESULTS: Mean IOP was similar between GS and POAG groups (15.6 ± 3.47 vs 15.6 ± 2.83 mmHg, p = 0.90) as was IOP peak at 6 AM (21.7 ± 3.85 vs 21.3 ± 3.80 mmHg, p = 0.68). Statistically significant negative correlations were found in POAG group between IOP at 6 AM and RNFLT in global (rs = -0.543; p < 0.001), inferior (rs = -0.540; p < 0.001), superior (rs = -0.405; p = 0.009), and nasal quadrants (rs = -0.561; p < 0.001). Negative correlations were also found between ∆IOP and RNFLT in global (rs = -0.591; p < 0.001), and all other sectors (p < 0.05). In GS IOP at 6 AM correlated only with inferior quadrant (rs = -0.307; p = 0.047). CONCLUSION: IOP at 6 AM and ∆IOP had negative correlations with RNFLT quadrants in POAG. In GS this correlation occurred between IOP at 6 AM and inferior quadrant. These findings may indicate potential risk factors for glaucoma progression.

Screening for Novel LOX and SOD1 Variants in Keratoconus Patients from Brazil.

PURPOSE: To investigate the presence of the variants of lysyl oxygenase (LOX) and superoxide dismutase 1 (SOD1) genes in Brazilian patients with advanced keratoconus. METHODS: Donor genomic DNA extracted from blood samples was screened for 5'UTR, exonic LOX, and SOD1 variants in a subset of 26 patients presenting with advanced keratoconus (KISA > 1000% and I-S > 2.0) by Sanger sequencing. The impact of non-synonymous amino acid changes was evaluated by SIFT, PMUT, and PolyPhen algorithms. The Mutation Taster tool was used to evaluate the potential impact of formation of new donor and acceptor splice sites in the promoter region of affected volunteers carrying sequence variants. A 7-base SOD1 deletion (IVS2 + 50del7bp) previously associated with keratoconus was screened in 140 patients presenting classical keratoconus by gel fragment analysis, and positive samples were sequenced for confirmation. RESULTS: We found an unreported missense variant in LOX exon 6 in one heterozygous patient, leading to substitution of proline with threonine at residue 392 (p. Thr392Pro) of LOX protein sequence. This mutation was predicted to be potentially damaging to LOX protein. Another LOX variant, Arg158Gln, was also detected in another patient but predicted to be non-pathogenic. Two additional new polymorphisms in LOX 5'UTR region (-116C > T and -58C > T) were found in two patients presenting with advanced keratoconus and were predicted to modulate or create donor/acceptor splice sites in LOX transcripts. Additionally, SOD1 deletion was detected in one patient presenting with severe keratoconus, not in control samples. CONCLUSION: We described three novel LOX polymorphisms identified for the first time in Brazilian patients with advanced keratoconus, as well as a previously described SOD1 deletion strongly associated with keratoconus. A possible role of these variants in modulating transcript levels in the cornea of affected individual requires further investigation.

Use of chitosan as pharmaceutical excipient in ocular drug delivery systems: Sterilization and pharmacokinetics.

The use of chitosan as a pharmaceutical excipient in the ocular field is already established. Nevertheless, some aspects related to its ocular administration, such as sterilization and excipient's pharmacokinetics, remain unclear. So, in this study, we evaluated those two relevant aspects, related to chitosan administration in eye. We used chitosan-based ocular inserts (CI) as formulation model. CI were produced by solvent/casting method and sterilized by saturated steam. Sterilization was confirmed by direct inoculation of inserts in suitable microbiological growth media. Physicochemical characterization of inserts before and after sterilization was performed. Results suggested that, although steam sterilization changed the arrangement of the matrix, the heat and the humidity did not modify the structure of the main polymeric chain. Pharmacokinetics of CI radiolabeled with technetium-99m (99m Tc) was assessed by scintigraphic images and ex vivo biodistribution study, after ocular administration in male Wistar rats. Scintigraphic and images analysis and ex vivo biodistribution study showed that the insert remained mainly in the eye until 6 hr after administration and its degradation products began to migrate to the abdominal cavity after 18 hr. Together, these data represent an important step forward the manufacturing and the clinical application of CI in the ophthalmic field.

Development and validation of analytical method by HPLC-DAD for determination of vasodilator active in pharmaceutical ophthalmic forms

The substance 4-Aminobenzamidine dihydrochloride (4-AD) is one of the degradation products of diminazene aceturate and has demonstrated antiglaucomatous potential. Glaucoma is the second leading cause of blindness worldwide; thus, new therapeutic alternatives must be studied, for example, the molecule 4-AD vehiculated into polymeric inserts for prolonged release. The present work aims to develop and validate an analytical method to quantify 4-AD in pharmaceutical ophthalmic forms. A HPLC was used with UV-Vis detector, at 290 ƞm and ACE® C18 column (125 × 4.6 mm, 5 µm), in which the mobile phase consists of phosphate buffer (pH 7.4) and triethylamine (30 mmol/L), under an isocratic flow of 1.0 mL/min. The retention time of 3.2 minutes was observed. The method was developed and validated in accordance with ANVISA recommendations and ICH guides. The linearity range was established between the concentrations 5 and 25 µg/mL (correlation coefficient r = 0.993). The accuracy, repeatability, and intermediate precision tests obtained a relative standard deviation less than or equal to 5%. In addition, the method was considered selective, exact. and robust, with pH being its critical factor. Therefore, the HPLC analysis method is robust and can be used to quantify 4-AD in pharmaceutical forms for ocular application.(AU)

Chitosan/hydroxyethyl cellulose inserts for sustained-release of dorzolamide for glaucoma treatment: In vitro and in vivo evaluation.

Eye drops containing hydrophilic drugs are commonly used to reduce intraocular pressure (IOP) in glaucoma patients, but compliance to the treatement is commonly reduced by frequent dosing and eventual systemic side effects. Sustained-release drug delivery systems, such as ocular inserts, can reduce dosing, limit systemic exposure, reduce side effects, and, then, improve patient adherence to therapy. Here, we developed and evaluated chitosan/hydroxyethyl cellulose-based ocular inserts for sustained release of dorzolamide, a hydrophilic drug. Dorzolamide inserts (DI) were produced by solvent/casting method and characterized by various physicochemical techniques. Pharmacokinetics studies were performed using scintigraphic images and ex vivo biodistribution. The effectiveness of inserts was tested in glaucomatous rats. Characterization studies showed that the drug strongly interacted with the polymeric matrix, but in vitro results showed that DI took only 3 h to release 75% of dorzolamide entraped. However, scintigraphic images and ex vivo biodistribution studies revealed that more than 50% of 99mTc-dorzolamide remained in the eye after 18 h of DI administration, while only about 30% of the drug remained in the eye after drops instilation. DI exerted significant hypotensive effect for two weeks, after single administration, while IOP values remained high in placebo and untreated groups. Eye drops were effective only during the treatment period. Only DI treatment prevented retinal ganglion cells death. Altogether, these findings evidenced the potential application of polymeric-based inserts for sustained release of dorzolamide in glaucoma management.