Fixed-combination Bimatoprost/Brimonidine/Timolol in Glaucoma: A Randomized, Masked, Controlled, Phase III Study Conducted in Brazil☆.

PURPOSE: Many patients with open-angle glaucoma eventually require >2 medications to lower their intraocular pressure (IOP). Fixed-combination ophthalmic solutions can be advantageous in patients who require multiple medications, but the number of fixed combinations combining 3 complementary IOP-lowering agents remains limited. This study assessed the efficacy and safety of a triple fixed combination (TFC) of bimatoprost 0.01%/brimonidine 0.15%/timolol 0.5% ophthalmic solution in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT), compared with a dual fixed combination (DFC) of brimonidine 0.2%/timolol 0.5%. METHODS: Patients with a baseline IOP of 23-34 mm Hg in both eyes and no history of IOP-lowering procedures were eligible for participation in this multicenter, double-masked, randomized, Phase III study. After washout of previous treatment (if applicable), patients were randomized to receive TFC or DFC twice daily in each eye for 3 months. The primary efficacy variable was the change from baseline in mean IOP in the worse eye at week 12 in the modified intent-to-treat (mITT) population. TFC was superior to DFC if the treatment difference (TFC - DFC) favored TFC at week 12 (P ≤ 0.05; 2-sample t test). Secondary and sensitivity analyses were also performed. Safety, including adverse events, was assessed at all visits. FINDINGS: The mITT/safety population included 185 patients (TFC, n = 90; DFC, n = 95). TFC superiority was demonstrated at all postbaseline visits (all, P < 0.001) through week 12 (week 12 treatment difference: ─2.17 mm Hg; 95% CI, ─3.12 to ─1.22). While treatment-related conjunctival hyperemia was more frequent with TFC than with DFC (47.8% vs 23.2%; P < 0.001), consistent with the additional presence of bimatoprost in TFC, most cases were mild and the numbers of patient discontinuations at week 12 were similar between the TFC and DFC groups (11 [12.2%] vs 7 [7.4%] patients; P = 0.266). No unexpected adverse events were reported. IMPLICATIONS: Compared with DFC, TFC provided superior IOP lowering throughout the primary efficacy period. An acceptable tolerability profile was observed through 12 months of use of TFC, offering an effective therapeutic option in patients with POAG or OHT who require multiple medications to control their IOP. Additional studies are required for the assessment of the long-term effects of TFC. ClinicalTrials.gov identifier: NCT01217606.

Hyperemia reduction after administration of a fixed combination of bimatoprost and timolol maleate to patients on prostaglandin or prostamide monotherapy.

OBJECTIVE: The aim of this study was to evaluate the change in hyperemia and intraocular pressure (IOP) in patients who switch from prostaglandin or prostamide to a fixed combination of prostamide and timolol maleate. DESIGN: A multicenter, longitudinal, noncontrolled, nonrandomized open trial was conducted. PARTICIPANTS: One hundred forty-four patients (282 eyes) were selected: 60 (41.6%) were on travaprost, 51 (35.4%) on bimatoprost, and 33 (22.9%) on latanoprost. All patients included were unable to attain adequate IOP control with monotherapy and had no contraindications to ß-blockers. INTERVENTION: Patients were treated with a fixed combination of bimatoprost and timolol maleate. Hyperemia was evaluated using a referential table, and IOP was measured at 8:00, 12:00, and 16:00 h both before and after 4 months of treatment. MAIN OUTCOME: IOP and hyperemia were compared at 2 time points: pretreatment and after 4 months. The mean of the 3 IOP measurements taken at various points during the day was considered for analysis. Generalized estimating equations were used for repeated measures and intereye dependency adjustments. RESULTS: Hyperemia and IOP were reduced in all 3 groups, with the same pattern for both eyes. The bimatoprost group had the highest levels of hyperemia before treatment when compared with the latanoprost as well as the travaprost group and had the greatest reduction in hyperemia after treatment (P < 0.01). Regarding IOP, all 3 groups had a significant reduction (P < 0.001), but the bimatoprost group had a lower pretreatment IOP when compared with the travaprost and latanoprost groups. CONCLUSION: A significant reduction in hyperemia was found after switching from monotherapy with prostaglandins or prostamide to a fixed combination of prostamide and a ß-blocker. IOP reduction was significant after the intervention in all 3 groups.

Presentation of glaucoma in an urban tertiary care hospital in South America: legal blindness and prevalence.

PURPOSE: To determine disease severity in glaucoma patients who presented to a tertiary care service for the first time and to determine the prevalence of different types of glaucoma. METHODS: Retrospective analysis of data of patients referred to the Glaucoma Service at the Santa Casa de Misericórdia de São Paulo, Brazil in 2007. A complete chart review from 448 patients was done; data regarding age, gender, ethnicity, family history, duration of the disease, previous treatment, best corrected visual acuity, cup-to-disc ratio, intraocular pressure, diagnosis and treatment were collected. Glaucoma was diagnosed by the presence of typical optic disk abnormalities, disregarding IOP values. RESULTS: 52.3% of patients presented visual acuity less than or equal to 20/200 and 67.7% presented cup-to-disc ratio between 0.8 and 1.0 in the worse-seeing eye; 13.4% of patients were considered legally blind. Primary open angle glaucoma was the most prevalent form of glaucoma (54.2%, 95% CI: 48.5-59.5) and chronic angle closure glaucoma was the second most frequent (11.5%, 95% CI: 8.25-15.5). CONCLUSION: A considerable rate of patients (almost 60% in the better-seeing eye and 70% in the worse-seeing eye) presented with advanced glaucoma. Strategies that create conditions for early diagnosis are deemed necessary to reduce glaucoma-related blindness in the Brazilian population.

CYP1B1 gene analysis in primary congenital glaucoma Brazilian patients: novel mutations and association with poor prognosis.

PURPOSE: To determine the spectrum of CYP1B1 gene mutations in Brazilian patients with primary congenital glaucoma, and to correlate the presence of alterations in the CYP1B1 gene sequence with clinical aspects of the disease. MATERIALS AND METHODS: Thirty nonrelated patients with primary congenital glaucoma were studied. Molecular analysis consisted of the codifying region sequencing (exons 2 and 3) and intron/exon boundaries. RESULTS: CYP1B1 gene mutations were present in 9 (30%) of the 30 patients. The structural changes in the CYP1B1 gene previously described in the literature and observed in our study were Q19X, P437L, A443G, g.4340delG, g.7901_79013delGAGTGCAGGCAGA, g.8182delG, and g.8214_8215delG. Three new mutations were observed: 4635delT, 4523delC, and L378Q, in addition to 3793T→C, R48G, A119S, L432V, D449D, and N453S polymorphisms. Patients carrying CYP1B1 gene mutations needed more surgical procedures to control intraocular pressure, either when both eyes were evaluated (P=0.003) or when the worst eye of the patient was analyzed (P=0.011). In relation to the number of affected eyes, all patients with mutations (n=9/9) developed bilateral glaucoma, whereas 11/21 patients without mutations in the CYP1B1 gene had bilateral glaucoma (P=0.013). CONCLUSIONS: In this group of primary congenital glaucoma patients, a 30% mutation frequency in the CYP1B1 gene was observed. The presence of mutations was associated with a more severe form of the disease, requiring more surgeries for intraocular pressure control and with a higher rate of bilateral cases.

Lack of association between optineurin gene variants T34T, E50K, M98K, 691_692insAG and R545Q and primary open angle glaucoma in Brazilian patients.

PURPOSE: To verify the frequencies of T34T, E50K, M98K, 691_692insAG, and R545Q variants in the optineurin (OPTN) gene in Brazilian subjects with primary open-angle glaucoma (POAG) and controls. PATIENTS AND METHODS: Ninety-nine patients with POAG and 100 normal controls were enrolled in this study. The frequency of alterations in the OPTN gene was analyzed by direct sequencing and enzymatic digestion of PCR products. RESULTS: None of the five alterations evaluated was significantly associated with POAG when compared to controls. However, the T34T silent change was present in greater frequency in POAG patients (37.37% vs. 23.00% in controls), while the R545Q change was more prevalent in controls (23.00% vs. 10.10% in POAG). The M98K and 691_692insAG presented with low frequencies in POAG patients (1.01% and 2.02%, respectively) and controls (2.00% and 2.00%, respectively). The E50K substitution was not observed. CONCLUSION: Our data show no association between the five evaluated variants and POAG in the Brazilian population.

[Sensitivity of size I stimulus in achromatic automated perimetry for detection of glaucomatous visual field defects: a comparative analysis with short wavelength automated perimetry and standard automated perimetry (SITA)]. / Sensibilidade do estímulo de tamanho I na perimetria computadorizada acromática para a detecção de defeitos glaucomatosos no campo visual: análise comparativa com as perimetrias de ondas curtas e acromática convencional (SITA).

PURPOSE: To compare sensitivity and specificity of achromatic perimetry with size I stimulus (WW-I) with standard automated perimetry (SITA strategy) and blue on yellow perimetry (SWAP) for early diagnosis of glaucoma. METHODS: Seventy-three eyes of 73 suspects, glaucomatous and normal subjects underwent automated perimetry with SITA 24-2, WW-I and SWAP. After application of specific criteria of abnormality, sensitivity, specificity, and the area under ROC (Receiver Operating Characteristic) curve were calculated for each of the examinations. The areas under the ROC curve were compared pair-wisely with the univariable Z test and significance set at 5%. RESULTS: WW-I displayed the greatest sensitivity (100%) and the lowest specificity (75.7%). SWAP revealed less sensitivity (69.4%); specificity, however, was higher (89.2%). Pairwise comparison of ROC curves showed no difference. CONCLUSION: WW-I revealed good sensitivity for the detection of early glaucomatous visual field defects. This technique adds to the available armamentarium for early functional diagnosis of glaucomatous optic neuropathy.

Localização e freqüência das alterações de campo visual no glaucoma primário de ângulo aberto na estratégia SITA (Swedish Interactive Threshold Algorithm) / Location and frequency of visual field defects as measured by SITA (Swedish Interactive Threshold Algorithm) strategy in primary open angle glaucoma

OBJETIVO: Caracterizar os defeitos de campo visual nos exames realizados com o perímetro Humphrey®, estratégia SITA - Swedish Interactive Threshold Algorithm - segundo sua freqüência e localização em pacientes com glaucoma primário de ângulo aberto (GPAA). MÉTODOS: Realizamos análise retrospectiva de 6.200 prontuários. Avaliamos o exame de campo visual dos pacientes que preenchiam os critérios de inclusão e os dividimos em glaucoma leve, moderado e grave de acordo com a classificação de Hodapp. Definimos os seguintes defeitos glaucomatosos: degrau nasal, escotoma paracentral, escotoma arqueado, escotoma Seidel, defeito temporal em cunha, diminuição generalizada de sensibilidade, escotoma anular e campo tubular. Utilizamos diagrama que correlaciona os pontos do campo visual com as regiões do disco óptico e avaliamos as regiões mais acometidas de acordo com a densidade de pontos comprometidos. A análise estatística foi realizada aplicando-se o teste t de Student. RESULTADOS: Selecionamos 152 pacientes com idade média de 66,5±9,6 por cento, sendo 59,9 por cento do sexo feminino. No glaucoma leve o defeito campimétrico mais freqüente foi o degrau nasal superior, seguido respectivamente pelo escotoma paracentral e degrau nasal inferior. A diminuição generalizada de sensibilidade, apesar de rara, ocorreu em 7,8 por cento desses pacientes. A região superior foi mais acometida que a inferior. CONCLUSÃO: O degrau nasal superior e o escotoma paracentral foram os defeitos mais freqüentemente observados no glaucoma primário de ângulo aberto em fase inicial pela estratégia SITA, e o hemicampo superior foi a região mais acometida. A diminuição generalizada de sensibilidade foi defeito glaucomatoso precoce.