A new poly(ortho ester)-based drug delivery system as an adjunct treatment in filtering surgery.

PURPOSE: Pharmacologic modulation of wound healing after glaucoma filtering surgery remains a major clinical challenge in ophthalmology. Poly(ortho ester) (POE) is a bioerodible and biocompatible viscous polymer potentially useful as a sustained drug delivery system that allows the frequency of intraocular injections to be reduced. The purpose of this study was to determine the efficacy of POE containing a precise amount of 5-fluorouracil (5-FU) in an experimental model of filtering surgery in the rabbit. METHODS: Trabeculectomy was performed in pigmented rabbit eyes. An ointmentlike formulation of POE containing 1% wt/wt 5-FU was injected subconjunctivally at the site of surgery, during the procedure. Intraocular pressure (IOP), bleb persistence, and ocular inflammatory reaction were monitored until postoperative day 30. Quantitative analysis of 5-FU was performed in the anterior chamber. Histologic analysis was used to assess the appearance of the filtering fistula and the polymer's biocompatibility. RESULTS: The decrease in IOP from baseline and the persistence of the filtering bleb were significantly more marked in the 5-FU-treated eyes during postoperative days 9 through 28. Corneal toxicity triggered by 5-FU was significantly lower in the group that received 5-FU in POE compared with a 5-FU tamponade. Histopathologic evaluation showed that POE was well tolerated, and no fibrosis occurred in eyes treated with POE containing 5-FU. CONCLUSIONS: In this rabbit model of trabeculectomy, the formulation based on POE and containing a precise amount of 5-FU reduced IOP and prolonged bleb persistence in a way similar to the conventional method of a 5-FU tamponade, while significantly reducing 5-FU toxicity.

Baerveldt implant in refractory glaucoma: long-term results and factors influencing outcome.

PURPOSE: To evaluate the clinical outcome of patients who received a Baerveldt implant for refractory glaucoma and to identify factors which may influence the outcome. METHODS: Retrospective study including 51 eyes of 51 patients with medically uncontrolled glaucoma who underwent Baerveldt implant surgery between June 1994 and December 1998. Criteria for success were intraocular pressure (IOP) < or = 21 mmHg and > 6 mmHg, necessity of further antiglaucoma medications, absence of additional glaucoma surgery and no loss of light perception. RESULTS: Over a mean follow-up of 37.6 (SD: +/-18.8) months, the mean intraocular pressure decreased from 34.8 (+/-12.5) mmHg to 14.0 (+/-4.3) mmHg at month 60. Qualified success rate, achieved when IOP was below 21 mmHg and higher than 6 mmHg with medications was 25/48 (52%), complete success rate (same IOP limits without medication) was 14/48 (29%). Seven eyes had major complications or lost light perception. Postoperative visual acuity improved or remained within one Snellen line of the preoperative visual acuity in 35 patients (73%). Factors associated with a better prognosis were a preoperative visual acuity better than 20/400 and etiology of glaucoma. CONCLUSION: The Baerveldt implant is effective in lowering intraocular pressure in most patients with refractory glaucoma. Long-term results are promising with satisfactory IOP control.

Novel molecular mechanisms of neuronal and vascular protection in experimental glaucoma

Le glaucome est la deuxième cause de cécité irréversible dans le monde. La perte de vision qui se produit lors du glaucome s’explique par une dégénérescence du nerf optique et une mort progressive et sélective des cellules ganglionnaires de la rétine (CRG). L'hypertension oculaire est un facteur de risque majeur dans le glaucome, mais des défauts du champ visuel continuent à se développer chez un contingent de patients malgré l'administration de médicaments qui abaissent la pression intraoculaire (PIO). Par conséquent, bien que la PIO représente le seul facteur de risque modifiable dans le développement du glaucome, son contrôle ne suffit pas à protéger les CRGs et préserver la fonction visuelle chez de nombreux patients. Dans ce contexte, j'ai avancé l'hypothèse centrale voulant que les stratégies de traitement du glaucome visant à promouvoir la protection structurale et fonctionnelle des CRGs doivent agir sur les mécanismes moléculaires qui conduisent à la mort des ces neurones. Dans la première partie de ma thèse, j'ai caractérisé l'effet neuroprotecteur de la galantamine, un inhibiteur de l'acétylcholinestérase qui est utilisé cliniquement dans le traitement de la maladie d'Alzheimer. Cette étude s’est basée sur l'hypothèse que la galantamine, en modulant l'activité du récepteur de l'acétylcholine, puisse améliorer la survie des CRGs lors du glaucome. Nous avons utilisé un modèle expérimental bien caractérisé d'hypertension oculaire induite par l’administration d'une solution saline hypertonique dans une veine épisclérale de rats Brown Norway. Les résultats de cette étude (Almasieh et al. Cell Death and Disease, 2010) ont démontré que l'administration quotidienne de galantamine améliore de manière significative la survie des corps cellulaires et des axones CRGs. La protection structurelle des CRGs s’accompagne d’une préservation remarquable de la fonction visuelle, évaluée par l'enregistrement des potentiels évoqués visuels (PEV) dans le collicule supérieur, la cible principale des CRGs chez le rongeur. Une autre constatation intéressante de cette étude est la perte substantielle de capillaires rétiniens et la réduction du débit sanguin associé à la perte des CRGs dans le glaucome expérimental. Il est très intéressant que la galantamine ait également favorisé la protection de la microvascularisation et amélioré le débit sanguin rétinien des animaux glaucomateux (Almasieh et al. en préparation). J'ai notamment démontré que les neuro-et vasoprotections médiées par la galantamine se produisent par iv l'activation des récepteurs muscariniques de l'acétylcholine. Dans la deuxième partie de ma thèse, j'ai étudié le rôle du stress oxydatif ainsi que l'utilisation de composés réducteurs pour tester l'hypothèse que le blocage d'une augmentation de superoxyde puisse retarder la mort des CRG lors du glaucome expérimental. J'ai profité d'un composé novateur, un antioxydant à base de phosphineborane (PB1), pour tester sur son effet neuroprotecteur et examiner son mécanisme d'action dans le glaucome expérimental. Les données démontrent que l'administration intraoculaire de PB1 entraîne une protection significative des corps cellulaire et axones des CRGs. Les voies moléculaires conduisant à la survie neuronale médiée par PB1 ont été explorées en déterminant la cascade de signalisation apoptotique en cause. Les résultats démontrent que la survie des CRGs médiée par PB1 ne dépend pas d’une inhibition de signalisation de protéines kinases activées par le stress, y compris ASK1, JNK ou p38. Par contre, PB1 induit une augmentation marquée des niveaux rétiniens de BDNF et une activation en aval de la voie de survie des ERK1 / 2 (Almasieh et al. Journal of Neurochemistry, 2011). En conclusion, les résultats présentés dans cette thèse contribuent à une meilleure compréhension des mécanismes pathologiques qui conduisent à la perte de CRGs dans le glaucome et pourraient fournir des pistes pour la conception de nouvelles stratégies neuroprotectrices et vasoprotectrices pour le traitement et la gestion de cette maladie.

Role of Reactive Gliosis and Neuroinflammation in Experimental Glaucoma

Le glaucome est la principale cause de cécité irréversible dans le monde. Chez les patients atteints de cette pathologie, la perte de la vue résulte de la mort sélective des cellules ganglionnaires (CGR) de la rétine ainsi que de la dégénérescence axonale. La pression intraoculaire élevée est considérée le facteur de risque majeur pour le développement de cette maladie. Les thérapies actuelles emploient des traitements pharmacologiques et/ou chirurgicaux pour diminuer la pression oculaire. Néanmoins, la perte du champ visuel continue à progresser, impliquant des mécanismes indépendants de la pression intraoculaire dans la progression de la maladie. Il a été récemment démontré que des facteurs neuroinflammatoires pourraient être impliqués dans le développement du glaucome. Cette réponse est caractérisée par une régulation positive des cytokines pro-inflammatoires, en particulier du facteur de nécrose tumorale alpha (TNFα). Cependant, le mécanisme par lequel le processus neuroinflammatoire agit sur la mort neuronale reste à clarifier. L’hypothèse principale de ce doctorat propose que les facteurs pro-inflammatoires comme le TNFα et la phosphodiestérase 4 (PDE4) interagissent avec les mécanismes moléculaires de la mort neuronale, favorisant ainsi la survie et la protection des CGRs au cours du glaucome. Dans la première partie de ma thèse, J’ai utilisé un modèle in vivo de glaucome chez des rats Brown Norway pour montrer que l’expression du TNFα est augmentée après l'induction de l'hypertension oculaire. L'hypothèse spécifique de cette étude suggère que les niveaux élevés de TNFα provoquent la mort des CGRs en favorisant l'insertion de récepteurs AMPA perméables au calcium (CP-AMPAR) à la membrane cytoplasmique. Pour tester cette hypothèse, j’ai utilisé un inhibiteur sélectif de la forme soluble du TNFα, le XPro1595. L'administration de cet agent pharmacologique a induit une protection significative des somas et des axones des neurones rétiniens. L'évaluation de la perméabilité au cobalt a montré que le TNFα soluble est impliqué dans l'insertion de CP-AMPAR à la membrane des CGRs lors du glaucome. L’exposition des neurones à une pression oculaire élevée est à l’origine de la hausse de la densité membranaire des CP-AMPARs, grâce à une diminution de l’expression de la sous-unité GluA2. La présence de GluA2 au sein du récepteur ne permet pas l’entrée du calcium à l’intérieur de la cellule. L'administration intraoculaire d’antagonistes spécifiques des CP-AMPARs promeut la protection des somas et des axones des CGRs. Ces résultats montrent que les CP-AMPARs jouent un rôle important dans la pathologie du glaucome. Dans la deuxième partie de ma thèse, j’ai caractérisé l'effet neuroprotecteur d’un inhibiteur de la PDE4, l’ibudilast, dans notre modèle de glaucome. L'hypothèse spécifique s’oriente vers une atténuation de la réponse neuroinflammatoire et de la gliose par l’administration d’ibudilast, favorisant ainsi la protection neuronale. Les résultats montrent que dans les rétines glaucomateuses, l’ibudilast diminue la gliose et l'expression de plusieurs facteurs tels que le TNFα, l'interleukine-1β (IL-1β), l’interleukine-6 (IL-6) et le facteur inhibiteur de la migration des macrophages (MIF). Chez les rats glaucomateux, nous avons observé une expression notable de PDE4A dans les cellules de Müller, qui est en corrélation avec l'accumulation de l’AMP cyclique (AMPc) dans ces cellules après un traitement d’ibudilast. Finalement, nous avons démontré que la protection des CGRs via l’administration d’ibudilast est un mécanisme dépendent de l’AMPc et de la protéine kinase A (PKA). En conclusion, les résultats présentés dans cette thèse identifient deux mécanismes différents impliqués dans la perte des CGRs au cours du glaucome. Ces mécanismes pourraient fournir des perspectives potentielles pour le développement de nouvelles stratégies de traitement du glaucome.

Macrodisco y glaucoma en individuos estudiados con tomografía óptica coherente

Introducción: El glaucoma representa la tercera causa de ceguera a nivel mundial y un diagnóstico oportuno requiere evaluar la excavación del nervio óptico que está relacionada con el área del mismo. Existen reportes de áreas grandes (macrodiscos) que pueden ser protectoras, mientras otros las asocian a susceptibilidad para glaucoma. Objetivo: Establecer si existe asociación entre macrodisco y glaucoma en individuos estudiados con Tomografía Optica Coherente (OCT ) en la Fundación Oftalmológica Nacional. Métodos: Estudio transversal de asociación que incluyó 25 ojos con glaucoma primario de ángulo abierto y 74 ojos sanos. A cada individuo se realizó examen oftalmológico, campo visual computarizado y OCT de nervio óptico. Se compararon por grupos áreas de disco óptico y número de macrodiscos, definidos según Jonas como un área de la media más dos desviaciones estándar y según Adabache como área ≥3.03 mm2 quien evaluó población Mexicana. Resultados: El área promedio de disco óptico fue 2,78 y 2,80 mm2 glaucoma Vs. sanos. De acuerdo al criterio de Jonas, se observó un macrodisco en el grupo sanos y según criterio de Adabache se encontraron ocho y veinticinco macrodiscos glaucoma Vs. sanos. (OR=0,92 IC95%=0.35 – 2.43). Discusión: No hubo diferencia significativa (P=0.870) en el área de disco entre los dos grupos y el porcentaje de macrodiscos para los dos grupos fue similar, aunque el bajo número de éstos no permitió concluir en términos estadísticos sobre la presencia de macrodisco y glaucoma.

Efeito da brimonidina na circulação retrobulbar em pacientes com glaucoma: estudo com Doppler colorido

Objetivo: Avaliar o efeito do tartarato de brimonidina a 0,2% tópico, instilado de 12/12 horas, na circulação retrobulbar em pacientes portadores de glaucoma. Métodos: Foram estudados os 2 olhos de 16 pacientes portadores de glaucoma primário de ângulo aberto e glaucoma crônico de ângulo estreito com iridotomia. Usando o Doppler colorido foram avaliados: velocidade sistólica máxima, velocidade diastólica final e índice de resistência das artéria central da retina, artéria ciliar posterior curta temporal e artéria oftálmica. As avaliações foram feitas antes e depois do uso da brimonidina. Resultados: O tartarato de brimonidina a 0,2% aumentou significativamente a velocidade sistólica máxima (28,24 para 34,23 cm/seg) e velocidade diastólica final (6,62 para 8,10 cm/seg) no olho direito e reduziu o índice de resistência (0,75 para 0,71) no olho esquerdo da artéria oftálmica. Conclusão: O tartarato de brimonidina 0,2% 2x/dia aumentou significativamente a velocidade sistólica máxima e velocidade diastólica final e reduziu índice de resistência da artéria oftálmica de pacientes glaucomatosos. Este efeito sugere que a brimonidina pode beneficiar pacientes glaucomatosos com insuficiência vascular na cabeça do nervo óptico.

Glaucoma secundário em cães e gatos

Glaucoma is a syndrome that affects animals of different species and in different moments of his life, having variables causes in function of this presentation. It is an ophthalmic emergency that may develop irreversible vision damage as well as the patient's aesthetic presentation. Increased intraocular pressure, presence of engorged episcleral vessels, conjunctival hyperemia, pain, anterior uveitis, lens luxation and buftalmia are commonly clinical signs presented by dogs while in cats, signs are less expressive, noting mydriasis, mild ciliary injection and progressive buftalmia. For diagnosis are carried out three basic procedures: tonometry, gonioscopy and ophthalmoscopy. The treatment can establish with medical therapy with or without surgical intervention, however, at some point it will be necessary to perform enucleation or evisceration of the eye bulb.

Efeitos do citrato de sildenafila sobre a neuroproteção na neuropatia óptica, em ratos (Lewis/SsNHsd) com glaucoma agudo

Pós-graduação em Cirurgia Veterinária - FCAV

Safety and efficacy of fixed-combination travoprost/timolol in patients with open-angle glaucoma or ocular hypertension not controlled with timolol monotherapy

To assess the intraocular pressure (IOP)-lowering effect of travoprost 0.004%/timolol 0.5% fixed-dose combination (TRAV/TIM-FC) in patients not achieving the target IOP of ≤18 mmHg while on timolol 0.5% (TIM) monotherapy. A multicenter, prospective, open-label study (NCT01336569) was conducted in patients with open-angle glaucoma or ocular hypertension. Eligible patients were receiving TIM monotherapy with a screening/baseline IOP of 19-35 mmHg in ≥1 eye. TIM was discontinued on the baseline visit day (no washout period) and TRAV/TIM-FC was initiated and administered once daily at 8 pm for 4-6 weeks. The primary efficacy variable was mean change in IOP from TIM-treated baseline to study end, measured by Goldmann applanation tonometry. Results were analyzed by analysis of variance and paired samples t-test (5% significance). A total of 49 patients were enrolled (mean age, 63 [range, 42-82] years; 55.1% White; 73.5% women), and 45 were included in the intent-to-treat (ITT) population. Mean duration of treatment with TRAV/TIM-FC was 31 days. Mean ± standard deviation IOP reduction from baseline (TIM) to the follow-up visit (TRAV/TIM-FC) was -5.0±3.6 mmHg. IOP decreased significantly (P<0.0001) from baseline (22.1±2.6 mmHg) to study end (17.1±3.9 mmHg) in the ITT population, with a mean IOP reduction of 22.3%. Most patients (n=33/45; 73.3%) achieved IOP ≤18 mmHg. Two patients experienced a total of four adverse events (AEs), including a patient who reported one serious AE (enterorrhagia) that was considered unrelated to treatment, and a patient who reported one event each of drug-related redness, pruritus, and foreign body sensation. Most patients (n=47/49; 95.9%) reported no AEs. TRAV/TIM-FC lowered IOP in patients who were not at target IOP while receiving TIM monotherapy, with most patients achieving an IOP ≤18 mmHg with TRAV/TIM-FC. TRAV/TIM-FC was well tolerated in this population.

Experimental glaucoma model (ischemia and reperfusion): histology, morphometry, protein and gene espression of apoptosis pathway

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Risk factors for blindness in patients with open-angle glaucoma followed-up for at least 15 years

Purpose: To determine the proportion of blindness and investigate the relationships between risk factors based on clinical characteristics and development of blindness in patients with primary open-angle glaucoma (POAG) treated for at least 15 years. Methods: A retrospective observational chart review was performed with 403 patients referred to a tertiary level hospital, each with a diagnosis of primary open-angle glaucoma, treated for at least 15 years. Blindness attributable to glaucoma was defined based on visual acuity and/or visual field tests. Variables considered to be possible risk factors for blindness were evaluated using odds ratio (OR), confidence interval (95% CI), and univariate and multivariate analyses. Results: Thirty-one patients became blind [13/53 (24.5%) - unilaterally and 18/53 (34%) - bilaterally] during the follow-up period of treatment (19.5 +/- 4.6 years, range 15-31 years). Multivariate statistics with regression analysis revealed that persistency on initial therapy <= 6 months was significantly associated with blindness, both unilateral (OR: 8.4; 95% CI: 1.3-56.4) and bilateral (OR: 7.2; 95% CI: 1.3-39.6). Other potential factors such as race, age, gender or number of medications were not associated with blindness. Conclusion: Blindness from primary open-angle glaucoma was not uncommon in this population of treated patients after the long follow-up period proposed. Persistence rates with the first therapy, as measured by a medical decision to change, were low. Persistence <= 6 months was statistically associated with the development of unilateral and bilateral blindness from glaucoma.

Translational neuroprotection research in glaucoma: a review of definitions and principles

The maintenance of vision, through prevention and attenuation of neuronal injury in glaucoma, forms the basis of current clinical practice. Currently, the reduction of intraocular pressure is the only proven method to achieve these goals. Although this strategy enjoys considerable success, some patients progress to blindness; hence, additional management options are highly desirable. Several terms describing treatment modalities of neuronal diseases with potential applicability to glaucoma are used in the literature, including neuroprotection, neurorecovery, neurorescue and neuroregeneration. These phenomena have not been defined within a coherent framework. Here, we suggest a set of definitions, postulates and principles to form a foundation for the successful translation of novel glaucoma therapies from the laboratory to the clinic.

[Treatment of uveitis-associated refractory ocular hypotony with topical ibopamine]

BACKGROUND: Ibopamine is a non-selective dopamine- and adrenalin-receptor agonist that has been shown to cause pupillary dilation and an increase in aqueous humour secretion. This novel drug can be used as a mydriatic agent, as a provocative test in open-angle glaucoma, and for the treatment of persisting ocular hypotony. HISTORY AND SIGNS: This 47-year-old man had a history of uveitis associated with Crohn's disease. Six years after deep sclerectomy for uveitic secondary glaucoma, he developed severe hypotony in his left eye with drop of visual acuity (VA). The hypotony did not respond to topical steroid treatment. 2 % Ibopamine solution was ordered t. i. d. concomitant to 1 % prednisolone acetate. THERAPY AND OUTCOME: Intraocular pressure (IOP) began to rise after 3 weeks of Ibopamine treatment and returned to normal (12 mmHg) with continuous recovery of VA after 8 weeks. Ibopamine was discontinued at an IOP of 16 mmHg after a course of 12 weeks. IOP and VA remained stable during the 12-month follow-up period. CONCLUSIONS: Ibopamine 2 % eye drops in combination with topical steroids are a therapeutic option in uveitis-associated ocular hypotony.

Long-term outcome of trans-scleral diode laser cyclophotocoagulation in refractory glaucoma

BACKGROUND: Long-term outcome and complications of diode laser cyclophotocoagulation (DCPC) may be important, since eyes, once treated with DCPC, are less likely to be subjected to other types of interventions in the further follow-up. METHODS: Retrospective review of 131 eyes of 127 patients treated from 2000 through 2004. Success was defined as intraocular pressure (IOP) at last visit 6-21 mm Hg; hypotony: IOP treatment sessions per eye was 1.54, 89% of the eyes having 1 or 2 sessions; overall re-treatment rate: 38.9%. Mean total laser energy delivered per eye: 133.9 (73.7) J; mean energy per treatment episode: 86.8 (22.0) J. Eyes with 3 or more treatments (11%) had a significantly larger proportion of post-traumatic glaucoma, and patients were significantly younger. All eyes had refractory glaucomas on maximal medication, neovascular glaucoma (NVG) representing the largest subgroup (61%). IOP decreased from 36.9 (10.7) mm Hg pretreatment to 15.3 (10.4) mm Hg at the end of FU. Success was noted in 69.5% (91 eyes), failure (non-response) in 13%. Hypotony occurred in 17.6% eyes, of which 74% had NVG. Hypotony developed after mean 19.3 (11.0) months, range 6 to 36; with 96% of these eyes having received only 1 or 2 treatments; delivered energy did not differ from that in the successful eyes. CONCLUSIONS: DCPC is an efficient treatment for refractory glaucoma. Hypotony, the most common complication, may develop as late as 36 months post-treatment. Diagnostic category and age seem to influence the outcome stronger than laser protocol and delivered energy.

[Positive ibopamine provocative test in normal-tension glaucoma suspects]

BACKGROUND: Ibopamine is an alpha-adrenergic agent and causes an elevation of intraocular pressure in eyes with increased outflow resistance. It has been proposed as a test substance for the detection of early ocular hydrodynamic disorders. PATIENTS AND METHODS: A total of 64 normal-tension glaucoma suspect eyes without anti-hypertensive treatment were enrolled. A daily pressure curve was registered with measurements at 7:00 am, 8:00 am, 12:00 am, 17:00 pm using an applanation tonometer and a contour tonometer followed by instillation of ibopamine 2% in both eyes. Tonometry was performed every 15 minutes during the following hour. An IOP increase of > 2.0 mmHg was considered positive. RESULTS: The positive test group showed a significant pressure increase from 18.04 to 22.06 mmHg. Ocular pulse amplitude increased from 2.96 to 3.97 mmHg and was positively correlated with the pressure. Intraocular pressure was unchanged in the negative test group. Central corneal thickness was not significantly different in the two groups (p = 0.32). CONCLUSIONS: Ibopamine 2% eye drops have a positive pressure effect in 50% of suspected normal-tension glaucoma eyes and may differentiate between eyes with normal trabecular outflow capacity and eyes with increased resistance in the trabecular meshwork that are prone to pressure peaks and deterioration to glaucoma.