Eye (2002) 16, 39–43 2002 Nature Publishing Group All rights reserved 0950-222X/02 $25.00 www.nature.com/eye · MK Arici, M Sayici, MI Toker, H Erdog˘ an and CLINICAL STUDY A short term study of A Topalkara the additive effect of timolol and brimonidine on intraocular pressure Abstract intraocular pressure (IOP) by decreasing aqueous production and increasing Purpose To evaluate the additive ocular uveoscleral outflow.1,2 Brimonidine has been hypotensive effect of the combination of shown to effectively lower IOP in brimonidine and timolol on intraocular glaucomatous, ocular hypertensive and pressure (IOP) reduction in patients with normotensive eyes.3–5 glaucoma. It has been shown that brimonidine was Methods This was a prospective, well tolerated, safe and clinically effective in randomized, double-masked, crossover study lowering IOP.6 However, the cardiopulmonary in 20 patients with primary open angle effects of brimonidine were limited to a slight glaucoma (POAG) on therapy receiving reduction in systolic blood pressure during timolol maleate 0.5% twice daily, with IOP recovery from exercise and at 4 h after greater than or equal to 22 mmHg in one instillation.7 eye. The treatment period was 3 weeks and In many countries, the ␤-adrenergic during this period timolol + brimonidine or antagonists are often the first monotherapy timolol + placebo were applied topically choice of glaucoma or ocular hypertension twice daily and IOP, blood pressure, heart therapy. Many patients treated with this single rate and pupil size were measured. medication required adjunctive therapy to Results Combined therapy (timolol + adequately reduce IOP in the long term. brimonidine) had clinically significant IOP- Alpha adrenergic agonists, latanoprost, lowering effect during the treatment period dorzolamide and pilocarpine can be added to (P Ͻ 0.01). The mean diurnal IOP was this therapy. There was no placebo-controlled significantly reduced by an average of 5.1–5.9 study on the brimonidine and timolol maleate mmHg (21.2–24.5%) compared with baseline combination. For this reason we have value. The timolol + placebo combination performed this clinical placebo-controlled had no clinically significant IOP-lowering study of the additive effect of brimonidine effect (P Ͼ 0.05). No clinically significant tartrate 0.2% and timolol maleate 0.5% in a side effects were observed during the short-term period. treatment of both groups. Conclusions This study showed that the Department of Ophthalmology combination of topically applied Patients and methods Cumhuriyet University brimonidine and timolol cause a marked and School of Medicine sustained IOP reduction. Twenty patients were enrolled into this Sivas, Turkey Eye (2002) 16, 39–43. DOI: 10.1038/ prospective, randomized, double-masked, sj/EYE/6700035 crossover study which was conducted from Correspondence: MK Arici November 1998 to December 2000. The Cumhuriyet U¨ niversitesi Tip patients who had POAG and uncontrolled Faku¨ ltesi Keywords: glaucoma; timolol; brimonidine IOP (IOP Ն 22 mmHg) and were receiving Go¨ z ABD-58140 timolol maleate 0.5% alone were included in Sivas, Turkey + this study. One eye of each patient was Tel: 90 346 Introduction 2191010/2225 selected for treatment and in the patients with Fax: +90 346 2191284 Brimonidine tartrate 0.2% is an effective bilateral glaucoma, the eye with the higher E-mail: kemalariciȰ alpha2 adrenergic agonist, that lowers IOP was chosen. hotmail.com Effect of timolol and brimonidine on IOP MK Arici et al 40 All patients met the following criteria: age older than Commercially available timolol (Cusimolol, Alcon 22 years, a clinical diagnosis of primary open-angle Cusi, SA, El Masnou, Spain), brimonidine (Alphagan, glaucoma, patients already receiving timolol twice Allergan Inc, Irvine, CA, USA) and artificial tears daily, corrected visual acuity of 20/80 or better in each (Liquifilm Tears, Allergan) were used. Diurnal IOP, eye. blood pressure and heart rate were defined as the Patients were excluded from the study for any of the mean value over the day, based on the values obtained following reasons: active ocular infection and ocular at 9 am, 3 pm, and 9 pm. disease other than glaucoma (blepharitis or cataract The results are presented as the mean Ϯ standard e.t), use of systemic and topical medications except deviation. RM-ANOVA (Repeated measurements- timolol, prior treatment with any ocular surgery or analysis of variance) tests were used for statistical laser therapy, contraindications to the use of alpha- analysis of diurnal IOP, blood pressure and heart rate adrenoreceptor agonist, female patients who were changes from baseline values. Wilcoxon signed rank pregnant, lactating, or unstable cardiopulmonary test was used for statistical evaluation of differences in disease. pupil size. Mann–Whitney U test was used for The patients were informed about this study and a statistical analysis between the timolol + brimonidine signed informed consent form was obtained from all and timolol + placebo group. Statistical calculations patients before study entrance. This was approved by were carried out using the SPSS (9.05 for Windows Cumhuriyet University, Faculty of Medicine Ethics version) package (SPSS Inc, Chicago, IL, USA). A P Committee. Medical and ocular history were obtained value Ͻ0.05 was considered statistically significant. from all patients before starting the study. Subsequently, all patients underwent slit-lamp Results biomicroscopy, gonioscopy, fundus examination, visual field examination and IOP measurements. Heart rate, Twenty patients were included in the study, 8 (40%) blood pressure and pupil size were also recorded. All women and 12 (60%) men with a mean age of 62.2 Ϯ IOP measurements were performed using a Goldmann 8.6 years (46–72 years). All patients were white and applanation tonometer; with the scale masked for the had POAG. The patients had been treated with timolol investigator, the tonometer scale was read by an for a mean of 9.05 Ϯ 3.7 months (range 6–15) prior to assistant. Three consecutive readings were taken at the study. each time, and the mean of the three values was used The mean IOP before and after the treatment period in the statistical analyses. The heart rate and blood is presented in Table 1 for each treatment group. The pressure were measured in a resting position. Pupil mean baseline diurnal IOP for patients receiving diameter was measured with a millimeter ruler in the timolol + brimonidine and timolol + placebo was 24.1 same room and under constant illumination while Ϯ 3.7 mmHg and 24.3 Ϯ 5.3 mmHg respectively. The subjects fixed on an object about 6 m away with the difference between mean baseline IOP for both groups other eye. Throughout the study, patients were was not statistically significant (P Ͼ 0.05). monitored for signs and symptoms of adverse effects The mean diurnal IOP of 1, 2 and 3 weeks was and at all time points biomicroscopic evaluation was lower in the timolol + brimonidine group than in the performed. timolol + placebo group (P Ͻ 0.05). On day 0 (baseline day), IOP, heart rate, blood The timolol + brimonidine group showed a pressure and pupil size were measured at 9 am, 3 pm statistically significant decrease in IOP at each time and 9 pm. Baseline values were obtained by calculating period when compared with their baseline values and the mean of the 9 am, 3 pm and 9 pm values. After the timolol + placebo group (P Ͻ 0.01). In this group, these measurements were obtained, either brimonidine further mean diurnal IOP reductions at the first, tartrate 0.2% or placebo were applied twice daily for 3 second and third week were 5.1 mmHg (21.2%), 5.9 weeks to the patients receiving timolol maleate 0.5% mmHg (24.5%), 5.7 mmHg (23.6%), respectively (P Ͻ twice daily. At the end of first, 2nd and 3rd weeks, 0.01). Further IOP reductions at the first, second and IOP, heart rate, blood pressure and pupil size were third week are given in Table 2 for each time period. measured for each day at 9 am, 3 pm, and 9 pm. After The maximum IOP lowering effect was seen on week a wash-out period (4 weeks) during which only timolol 2. While maximum (peak) reduction of IOP was seen was used, patients received timolol plus other test at 9 am, minimum (non-peak) reduction of IOP was medication for 3 weeks. seen at 3 pm. In the timolol + placebo group there Timolol was applied at 7 am and 7 pm. Test were no significant reductions in IOP at all time medications had been applied 5 min after each timolol periods when compared with their baseline values (P dose. Ͻ 0.05). Eye Effect of timolol and brimonidine on IOP MK Arici et al 41 Table 1 Baseline and after treatment mean intraocular pressure (mmHg ± SD) Time Timolol + Brimonidine Timolol + Placebo Baseline 1 week 2 weeks 3 weeks Baseline 1 week 2 weeks 3 weeks 9 am 24.8 ± 4.5 18.9 ± 5.3* 17.5 ± 4.5* 17.7 ± 6.2* 25.4 ± 4.1 24.4 ± 4.5** 25.5 ± 7.8** 25.1 ± 6.5** 3 pm 23.2 ± 3.6 19.9 ± 5.9* 18.8 ± 6.1* 19.1 ± 5.1* 23.3 ± 5.4 23.2 ± 5.3** 23.8 ± 4.3** 23.5 ± 7.2** 9 pm 24.3 ± 5.9 18.2 ± 3.1* 18.3 ± 5.4* 18.4 ± 4.3* 24.2 ± 5.1 24.1 ± 3.5** 23.9 ± 5.1** 23.7 ± 5.4** MD 24.1 ± 3.7 19.0 ± 5.0* 18.2 ± 5.3* 18.4 ± 5.4* 24.3 ± 5.3 23.9 ± 3.7** 24.4 ± 6.6** 24.1 ± 6.8** MD: Mean diurnal IOP. *P Ͻ 0.01 (compared with baseline value).