Assessment of corneal sublayer thickness changes in glaucoma patients using optical coherence tomography and correlation of epithelial layer thinning with dry eye monitoring.

BACKGROUND: In this study, we aimed to assess the central corneal epithelial thickness (CET), central corneal stromal thickness (CST), and total central corneal thickness (CCT) thinning relationships with dry eye development monitoring and underestimated measurement of intraocular pressure (IOP) in primary open-angle glaucoma (POAG) patients treated with timolol, dorzolamide, and brimonidine. METHODS: This longitudinal cohort study included 106 patients with POAG. All patients underwent a detailed ophthalmic examination. In addition, CET, CST, and CCT were measured using anterior segment optical coherence tomography (AS-OCT). Subsequently, the cohort was divided into three groups based on the therapy administered. The Tomec group received monotherapy with benzalkonium chloride (BAK)-preserved timolol + dorzolamide fixed combination. The Alphagan group received monotherapy with purite-preserved brimonidine, and the Combigan group received monotherapy with BAK-preserved timolol + brimonidine fixed combination. RESULTS: CET, CST, and CCT did not show a statistically significant decrease in the Alphagan group (p>0.05). However, the Tomec and Combigan groups showed significantly reduced measurements, except for stromal thickness (p<0.05). Finally, a significant positive correlation was found between changes in tear break-up time (TBUT) and CET during the follow-up period (r = 0.637, p = 0.001). CONCLUSIONS: CET and CCT thinning were higher in the Tomec and Combigan groups than in the Alphagan group. Furthermore, although CCT reduction was significant in the Tomec and Combigan groups, its effect on IOP underestimation was approximately 1%. Furthermore, the positive correlation between CET and TBUT suggests that CET measurement with AS-OCT may also be useful in dry eye monitoring.

DenTimol as A Dendrimeric Timolol Analogue for Glaucoma Therapy: Synthesis and Preliminary Efficacy and Safety Assessment.

In this work, we report the synthesis and characterization of DenTimol, a dendrimer-based polymeric timolol analog, as a glaucoma medication. A timolol precursor ( S)-4-[4-(oxiranylmethoxy)-1,2,5-thiadiazol-3-yl]morpholine (OTM) was reacted with the heterobifunctional amine polyethylene glycol acetic acid (amine-PEG-acetic acid, Mn = 2000 g/mol) via a ring opening reaction of an epoxide by an amine to form the OTM-PEG conjugate. OTM-PEG was then coupled to an ethylenediamine (EDA) core polyamidoamine (PAMAM) dendrimer G3 to generate DenTimol using the N-(3-(dimethylamino)propyl)- N'-ethylcarbodiimide hydrochloride (EDC)/ N-hydroxysuccinimide (NHS) coupling reaction. MALDI mass spectrometry, 1H NMR spectroscopy, and HPLC were applied to characterize the intermediate and final products. Ex vivo corneal permeation of DenTimol was assessed using the Franz diffusion cell system mounted with freshly extracted rabbit cornea. The cytotoxicity of DenTimol was assessed using the WST-1 assay. Our results show that DenTimol is nontoxic up to an OTM equivalent concentration of 100 µM. DenTimol is efficient at crossing the cornea. About 8% of the dendrimeric drug permeated through the cornea in 4 h. Its IOP-lowering effect was observed in normotensive adult Brown Norway male rats. Compared to the undosed eye, an IOP reduction by an average of 7.3 mmHg (∼30% reduction from baseline) was observed in the eye topically treated with DenTimol (2 × 5 µL, 0.5% w/v timolol equivalent) in less than 30 min. Daily dosing of DenTimol for a week did not cause any irritation or toxicity as confirmed by the histological examination of ocular tissues, including the cornea, ciliary body, and retina.

The fixed combination efficacy assessment in patients with secondary neovascular glaucoma and diabetes mellitus.

PURPOSE: To assess IOP-lowering efficacy of bimatoprost/timolol fixed combination (Ganfort®) in patients with diabetes mellitus (DM) and uncontrolled secondary neovascular glaucoma (NG). MATERIALS AND METHODS: Fifty patients (51 eyes) with uncontrolled secondary neovascular glaucoma and diabetes mellitus were enrolled in the study. All patients with an uncontrolled IOP have been proposed to switch current IOP-lowering therapy to Ganfort®. In case target IOP level was not reached filtration surgery was recommended. Ganfort® administration - once a day in the morning. RESULTS: IOP-lowering has been observed in all patients when switched to Ganfort®. Mean IOP level was almost 3-x lower versus baseline in 72.5% of patients (37 eyes). The patients achieved target IOP of 15-17 mmHg. As a result, no surgical intervention was required. Significant IOP-lowering has been observed in another group of patients (14 eyes, 27.5 %) nevertheless due to glaucoma progression, these patients are still subjected to surgical treatment. CONCLUSION: IOP-lowering fixed combination Ganfort® (Allergan) can be used in patients with secondary neovascular glaucoma and diabetes mellitus as a drug of choice to control the IOP level. Even in cases when target IOP is not achieved, Ganfort® can be administered in pre-operative period and helps to reduce postoperative complications.

[Mode of action, clinical profile and significance of beta-blockers in antiglaucoma therapy]. / Wirkmechanismen, klinisches Profil und Stellenwert von Betablockern in der antiglaukomatösen Therapie.

Beta-blockers are among the most important groups of drugs for glaucoma therapy. The advantages of beta-blockers are a good efficacy in primary and secondary types of glaucoma, different dosages, clinical experiences over decades, easy use in combination with all other glaucoma drugs, and low costs. Timolol is the most frequently used drug in fixed glaucoma medications. In comparison with other glaucoma drugs, beta-blockers have the most severe systemic side effects and may interact with other systemic medication.

Medical service encounters and payments associated with topical adjunctive therapy use of timolol for glaucoma.

BACKGROUND: Topical ß-blockers are commonly prescribed for primary open-angle glaucoma. Existing research is limited regarding respiratory or cardiovascular events that may result from using these topical ß-blockers. OBJECTIVE: To evaluate inpatient and outpatient service encounters and payments associated with the topical adjunctive use of the ß-blocker timolol for glaucoma. STUDY DESIGN: Retrospective data analysis using 2004-2011 IMS Lifelink Health Plan Claims Database. PATIENTS: Beneficiaries were included if they had a diagnosis of glaucoma (International Classification of Diseases-Ninth Revision-Clinical Modification [ICD-9-CM] code 365.xx) and at least 4 years of continuous enrollment and glaucoma medication use (defined as at least one pharmacy claim each year). Beneficiaries who had 4 years of observation with no timolol use were categorized as "controls" and those with 2 years of non-timolol glaucoma medication use followed by consecutive years of adjunctive timolol use were considered "cases." Beneficiaries with 2 years of non-timolol glaucoma medication use followed by 1 year in which they used timolol adjunctively and then a year without timolol use were considered "discontinuers." MAIN OUTCOME MEASURE: The rates of respiratory and cardiovascular disease in year 2 of the observation period were compared to the rates in year 3, and healthcare encounters and payments were also compared. RESULTS: There were 24,271 glaucoma patients who did not receive timolol (controls), 1,406 beneficiaries who were prescribed timolol in addition to other glaucoma medications and continued its use (cases), and 299 beneficiaries who used adjunctive timolol for only a single year (discontinuers). More than half of each group was less than 65 years of age (58 % of controls, 53 % of cases, 54 % of discontinuers, p < 0.05). The rate of respiratory disease increased in all groups from year 2 to year 3 of the observation period, with increases of 1.0 %, 1.4 % and 5.0 % points among controls, cases and discontinuers, respectively (all between-group comparisons significant at p < 0.05). There were similar changes in the rate of cardiovascular disease, with increases of 1.3 %, 1.5 % and 4.7 % points among controls, cases and discontinuers, respectively (all between-group comparisons significant at p < 0.05). These increases were generally lower for younger beneficiaries and greater for those 65 years and older. Comparing years 2 and 3 of the observation period, discontinuers more than doubled their average rate of all-cause inpatient hospitalizations (0.35-0.83 encounters annually), while this rate remained steady for cases and controls (between-group comparisons significant at p < 0.05). There was little change in this rate among patients less than 65 years of age. Among those aged 65 years and older, there was a substantial increase for discontinuers, with a tripling of the average annual rate of inpatient hospitalizations from 0.45 to 1.48 (all between-group comparisons significant at p < 0.05). In this older group, both discontinuers and cases experienced more than a 20 % increase in outpatient service encounters compared to only 9 % for controls (all between-group comparisons significant at p < 0.05). Overall, discontinuers would be expected to have average annual medical payments US$3,600 greater than controls and US$3,200 greater than cases. CONCLUSION: Adjunctive use of timolol by patients with glaucoma may be associated with increased respiratory and/or cardiovascular disease, hospitalizations and payments among patients for whom timolol may be contraindicated or who have yet undiagnosed manifestations of conditions for which it would be contraindicated.

The long-term outcomes of four alternative treatment strategies for primary open-angle glaucoma.

PURPOSE: To evaluate the long-term effects and costs of four treatment strategies for primary open-angle glaucoma compared to usual care. METHODS: Cost-effectiveness analyses with a lifelong horizon were made from a societal perspective. Data were generated with a patient-level model based on discrete event simulation. The model structure and parameter estimates were based on literature, particularly clinical studies on the natural course of glaucoma and the effect of treatment. We simulated heterogeneous cohorts of 3000 patients and explored the impact of uncertainty with sensitivity analyses. RESULTS: The incremental cost-effectiveness ratio (ICER) of initial treatment with a prostaglandin analogue compared with a ß-blocker was €12.931 per quality-adjusted life year (QALY) gained. A low initial target pressure (15 mmHg) resulted in 0.115 QALYs gained and €1550 saved compared to a gradual decrease from 21 to 15 mmHg upon progression. Visual field (VF) measurements every 6 rather than 12 months lead to health gains at increased costs (ICER €173,486 per QALY gained), whereas measurements every 24 months lead to health losses at reduced costs (ICER €21,516 per QALY lost). All treatment strategies were dominant over 'withholding treatment'. CONCLUSIONS: From a cost-effectiveness point of view, it seems advantageous to aim for a low intraocular pressure in all glaucoma patients. The feasibility of this strategy should therefore be investigated. Additionally, the cost-effectiveness outcomes of initiating monotherapy with a prostaglandin analogue and reducing the frequency of VF testing may be acceptable.

Balancing efficacy and tolerability of prostaglandin analogues and prostaglandin-timolol fixed combinations in primary open-angle glaucoma.

BACKGROUND: Lowering intraocular pressure (IOP) is currently the only therapeutic approach that preserves visual function in primary open-angle glaucoma. In making treatment decisions for first- and second-line therapy, the clinician needs to provide an appropriate balance of efficacy and tolerability. Prostaglandin analogues (PGAs) are frequently used as first-line monotherapy, because of their efficacy and low risk of systemic side effects. Similarly, PGA-based fixed combinations are frequently used in patients who progress or fail to achieve the target IOP. SCOPE: We have reviewed the literature on the management of primary open-angle glaucoma with PGAs, both as monotherapies and in fixed combinations. FINDINGS: In the clinical trial and meta-analysis data identified, bimatoprost 0.03% seems to be associated with a greater overall ability to lower IOP compared with latanoprost, travoprost or tafluprost, at the cost of a slightly higher incidence of conjunctival hyperaemia. Studies indicate that patients' adherence to treatment is generally better with PGAs than with many other monotherapies. In patients requiring more than one IOP-lowering agent, fixed combination treatments may provide improved adherence and tolerability benefits compared with concomitant use of individual treatments. Bimatoprost/timolol fixed combination appears to be slightly more efficacious than latanoprost/timolol or travoprost/timolol, and tolerability differences between the fixed combinations appear to be slight, probably because the addition of timolol to the PGA component lessens the associated hyperaemia. Surveys on EU physician attitudes appear largely in line with these clinical data. CONCLUSION: An appropriate balance between efficacy and tolerability ensures optimum IOP lowering and reduces the risk of non-adherence. PGAs largely fulfil this need as monotherapies and as components of combinations.

The clinical impact of 2 different strategies for initiating therapy in patients with ocular hypertension.

PURPOSE: To assess the impact of 2 strategies for initiating therapy in ocular hypertension (OH) on drug use, intraocular pressure (IOP), and blindness caused by glaucoma. METHODS: Using a simulation model, initiating therapy with timolol (strategy 1) and with latanoprost (strategy 2) was simulated for a hypothetic cohort of ocular hypertension patients with an initial IOP distribution (data of 1000 patients). Adjustment of therapy within 15 months and a subsequent lifelong follow-up, with an IOP dependent conversion to glaucoma, were modeled. The IOP lowering effect of medication (based on a meta-analysis) was applied by Monte Carlo simulation. Therapy could be maintained or changed, depending on the achieved IOP and side effects. Four drugs (latanoprost, timolol, brimonidine, dorzolamide) were used as monotherapy or in combination. Glaucoma conversion rate was based on literature. RESULTS: Treatment goal was achieved in both strategies in 90% by monotherapy. This was 60% for patients with initial IOP's of 30 mm Hg. The originally prescribed medication was maintained in 66% (1) and in 77% (2). IOP decreased with approximately 34%, from 25.4 mm Hg (mean) to 16.7 mm Hg (1) and to 16.5 mm Hg (2) Blindness per person within 18.7 years of life expectancy was 0.0923 years (1) and 0.0870 years (2), which corresponds to approximately 1 month. The difference between strategies was 2 days spent in blindness per patient. CONCLUSIONS: The difference in clinical effects of the strategies is small. This is largely owing to the key concept of a target pressure, which underlies both strategies.

Bimatoprost/timolol: a review of its use in glaucoma and ocular hypertension.

Topically administered bimatoprost 0.03%/timolol 0.5% ophthalmic solution (bimatoprost/timolol: Ganfort) comprises the synthetic prostamide bimatoprost (structurally related to prostaglandin F2 alpha) and the beta-adrenergic receptor antagonist timolol. Bimatoprost/timolol (one drop administered in the affected eye[s] once daily in the morning or evening) is an effective and well tolerated fixed combination for lowering intra-ocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension (OHT), including individuals uncontrolled on monotherapy with a beta-adrenergic receptor antagonist or prostaglandin analogue/prostamide.

A European perspective on costs and cost effectiveness of ophthalmic combinations in the treatment of open-angle glaucoma.

PURPOSE: Efficacy, safety, and cost implications are important considerations when choosing an ophthalmic treatment. Fixed-combination glaucoma medications containing brimonidine 0.2% and timolol 0.5%, or dorzolamide 2% and timolol 0.5%, were compared with brimonidine 0.2% and dorzolamide 2% that were used as adjunctive therapy to timolol 0.5%. METHODS: A literature review was conducted to determine the outcome parameters of intraocular pressure reduction and tolerability after 3 months of use of brimonidine or dorzolamide, each together with timolol as a fixed-combination or in concomitant therapy. Modelled cost-minimization and cost-effectiveness analyses were performed to investigate the economic consequences of ophthalmic therapy with brimonidine, dorzolamide, and timolol from a societal perspective. RESULTS: The literature review found that brimonidine and dorzolamide used as fixed combinations with timolol as well as in adjunctive therapy to timolol were equally effective and safe. Furthermore, in the European countries studied, the fixed combination of brimonidine/timolol represented a less costly option when compared to the fixed combination of dorzolamide/timolol evaluated over both a 3-month and a 12-month horizon. CONCLUSIONS: Brimonidine used as a fixed-combination therapy with timolol provided better cost value than dorzolamide/timolol in all the countries studied. For most countries, the fixed combination of brimonidine and timolol also provided better cost value than adjunctive therapy with brimonidine, which was more cost effective than adjunctive therapy with dorzolamide.

A 6-month assessment of bimatoprost 0.03% vs timolol maleate 0.5%: hypotensive efficacy, macular thickness and flare in ocular-hypertensive and glaucoma patients.

AIM: To compare 6 months of treatment with bimatoprost and timolol in terms of their hypotensive efficacy and secondary effects, including changes in macular thickness and the inflammatory reaction induced in the anterior chamber. METHODS: A prospective, randomized, parallel-group trial performed on 30 eyes of 30 patients per group. The main outcome measure was the difference between the IOP value taken between the baseline visit and the 6-month-visit. Macular thickness determined through optical coherence tomography and anterior chamber inflammation estimated using the laser flare meter was also evaluated. Adverse events were recorded during the study period. RESULTS: Bimatoprost treatment gave rise to a significantly lower mean IOP than timolol in all follow-up visits as from the first month (P<0.05). Bimatoprost achieved high percentage IOP reductions from baseline in a significantly higher proportion of patients (P<0.05). Macular thickness and anterior chamber flare failed to vary significantly both between the two groups and within each group during the 6-month evaluation (P>0.05). CONCLUSIONS: Bimatoprost 0.03% once daily showed a greater efficacy then timolol 0.05% twice daily in patients with elevated IOP. No significant differences were detected in macular thickness or anterior uveitis using optical coherence tomography and laser flare photometry.

Assessment of systemic adverse reactions induced by ophthalmic beta-adrenergic receptor antagonists.

To assess quantitatively the risks of ophthalmic beta-blocking agents for cardiovascular and respiratory adverse reactions, we analyzed the binding kinetics of beta-blocking agents to the beta-1 and beta-2 adrenoceptors. The relationship between the occupancies for beta-1 and beta-2 adrenoceptors and the effects on the exercise pulse rate or the forced expiratory volume in one second (FEV1) after topical administration of carteolol, befunolol, timolol and betaxolol was analyzed using a ternary complex model. The beta-1 and beta-2 receptor occupancies after ophthalmic administration were calculated to be quite high as well as those after oral administration. The maximum occupancies for beta-1 and beta-2 receptors after ordinary ophthalmic administration were 52% and 88% for carteolol, 52% and 61% for befunolol, 62% and 82% for timolol, and 44% and 3% for betaxolol, respectively. Concave relationships were obtained between a decrease in exercise pulse rate and the beta-1 receptor occupancy and between a decrease in FEV1 and beta-2 receptor occupancy, respectively. Nasolacrimal occlusion was estimated to decrease the exercise pulse rate and FEV1 by 65% and 50%, respectively. The beta-1 and beta-2 adrenoceptor occupancies were proved to be the most appropriate indicators for cardiac and pulmonary adverse reactions evoked by ophthalmic beta-blocking agents.

Ongoing clinical assessment of the safety profile and efficacy of brimonidine compared with timolol: year-three results. Brimonidine Study Group II.

OBJECTIVE: We compared the safety profile and efficacy of brimonidine 0.2% BID with those of timolol 0.5% BID over 3 years in patients with ocular hypertension and glaucoma. METHODS: Ninety-four eligible patients from an ongoing multicenter, interventional, double-masked clinical trial were followed through year 3, 48 receiving brimonidine 0.2% and 46 receiving timolol 0.5%. Study visits occurred at months 24, 27, 30, 33, and 36. The primary efficacy variable was mean reduction from baseline intraocular pressure (IOP) at trough. Visual acuity, visual fields, and safety variables (adverse events, ocular symptoms, heart rate, blood pressure, and laboratory test results) were monitored throughout the study. RESULTS: The 2 treatment groups were well matched, with no significant differences in demographic or clinical characteristics. Both drug regimens caused significant mean reductions from baseline IOP at trough during year 3 (P < 0.001), with no significant differences between groups at any study visit. The overall mean reduction from baseline IOP at trough was 5.02 mm Hg with brimonidine and 5.57 mm Hg with timolol (P = 0.383). Brimonidine caused reductions in IOP at trough that were equivalent to those with timolol at months 30 and 36 (within the 95% CI). Visual fields were unchanged or improved in 95% of patients in both treatment groups. Both drug regimens appeared to be safe and were well tolerated. Ocular allergy occurred in 2 brimonidine-treated patients (4.2%). There were no statistically significant differences in adverse-event reports and no clinically significant effects on any ocular or systemic safety variable in either group. CONCLUSIONS: Brimonidine 0.2% BID continues to appear to be safe, well tolerated, and effective in the long-term management of ocular hypertension and glaucoma. Over 3 years, it provided sustained IOP-lowering efficacy and visual-field preservation equal to those with timolol 0.5% BID.

Assessment of bronchial effects following topical administration of butylamino-phenoxy-propanol-acetate, an oculoselective beta-adrenoceptor blocker in asthmatic subjects.

1. Butylamino-phenoxy-propanol-acetate (BPPA) is a new topical oculoselective beta-adrenoceptor blocker for the reduction of intraocular pressure (IOP) in man. Its potency on the airways of normal subjects was identical with that of placebo. A study was carried out to determine the potential of BPPA to cause bronchoconstriction in mild asthmatics (FEV1 greater than or equal to 60% predicted) with normal IOP. 2. Twelve nonsmoking outpatients who bronchoconstricted to 0.25 or 0.50% of timolol eye drops (fall in FEV1 23.33 +/- 1.20% (mean +/- s.e. mean), range 16-30) were investigated in this double-masked, randomized, 3-period, crossover study. On three different occasions six incremental concentrations of BPPA (range: 0.1-2%; maximum cumulative concentration 4%), timolol (0.1-1%; 2%), and placebo were administered bilaterally until bronchoconstriction (decrease in FEV1 greater than or equal to 20% and in specific airway conductance (sGaw) greater than or equal to 35% simultaneously) or the maximum cumulative concentration was reached. 3. Airway response was measured as change in FEV1 and sGaw and dose-response curves to timolol, BPPA and placebo were performed. IOP was measured 3 h after the highest concentration of each study day. 4. Timolol caused dose-dependent falls in FEV1 and sGaw as well as clinical symptoms of respiratory distress in all subjects. The median cumulative concentrations of timolol required to decrease FEV1 by 20% and sGaw by 35% were 0.98% and 1.53%. Neither placebo (P greater than 0.05) nor BPPA (P greater than 0.05) caused a significant change in sGaw. A fall in FEV1 by 20% not accompanied by a simultaneous fall in sGaw by 35% was found in four subjects following BPPA and in five subjects following placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

A multi-centre, general practice assessment of a timolol/bendrofluazide combination ('Prestim') in the treatment of mild to moderate hypertension.

A fixed dose combination of 10 mg timolol and 2.5 mg bendrofluazide was evaluated in 1640 general practice patients with mild to moderate hypertension. This was an open study lasting 3 months with an initial 2-week placebo controlled run-in phase. Of the 1315 patients who were evaluable, 1169 (89%) became normotensive on a mean single daily dose of 1.75 tablets. Fifty-four (4%) patients were uncontrolled on a maximum dose of 4 tablets daily and 79 (6%) patients stopped therapy prematurely due to side-effects. A further 13 (1%) patients withdrew because of hypotension or bradycardia. Biochemical parameters stayed within normal values. Overall, the results showed that the combination of timolol and bendrofluazide was an effective and well accepted treatment for mild to moderate hypertension in a large and varied general practice population.

Epinephrine as the initial therapy in selected cases of ocular hypertension.

The authors believe that the epinephrines should be employed as the initial therapy in both primary open angle glaucoma and, when treated, ocular hypertension. Unlike pilocarpine, epinephrine does not produce miosis and accommodative spasm. Because of longer experience with epinephrine than with costly timolol, its longterm effectiveness and side effects are better known. Although the side effects of epinephrine are usually not serious, they may be intolerable to the patient. However, allergic blepharoconjunctivitis may be ameliorated by concomitant hydroxymesterone therapy. The availability of dipivalyl epinephrine (DPE) may decidedly shift the balance of the treatment of ocular hypertension, when indicated, to an epinephrine compound.