JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS Volume 31, Number 4, 2015 ª Mary Ann Liebert, Inc. DOI: 10.1089/jop.2014.0169
Short-Term Effect of Topical Brinzolamide 1%–Timolol 0.5% Fixed Combination on Human Central Corneal Thickness Erkan Celik,1 Elif Betul Turkoglu,2 Gonul Altun,1 and Gursoy Alagoz1
Abstract
Purpose: To evaluate the short-term effect of fixed combination of brinzolamide 1% and timolol 0.5% (FCBT) application on human central corneal thickness (CCT). Methods: This prospective clinical study included 97 patients having Nd:YAG laser posterior capsulotomy for posterior capsule opacification. Patients were randomized to receive apraclonidine hydrochloride 0.5% (APRA) (n = 48) or FCBT (n = 49) at 1 h before laser surgery. The baseline CCT was evaluated by ultrasonographic pachymetry from the central region *1 h before the laser procedure. CCT measurements were applied just before the laser application and then the first, second, and third hour, and the first, third, and seventh day after the Nd:YAG laser capsulotomy. Results: There was no statistically significant difference between the baseline intraocular pressures, CCTs, and demographic and clinical data (age, sex, surgery laser interval, total laser energy) of the APRA and the FCBT groups. The mean CCT values of the APRA group at the first, second, and third hour, and the first, third, and seventh day were 553.8 – 28.0, 551.4 – 35.3, 556.8 – 28.7, 552.6 – 27.5, 548.2 – 26.2, and 546.2 – 25.5 mm, respectively. The mean CCT values of the FCBT group at the first, second, and third hour, and the first, third, and seventh day were 544.21 – 34.4, 549.4 – 27.6, 555.94 – 33.1, 550.8 – 33.4, 547.2 – 33.6, and 544.9 – 33.4 mm, respectively. No statistically significant difference was detected between the 2 groups. Conclusion: The difference in CCT increase between both groups was not statistically significant at any followup visits. FCBT application does not have a short-term effect on CCT.
Introduction
T
opical medical therapy is the most common method of intraocular pressure (IOP) reduction, and many topical medications are available for lowering IOP.1 Despite a wide selection of effective single IOP-lowering medications, fixed combinations of topical hypotensive agents are frequently indicated to achieve more IOP reduction.2 Recently, a new fixed combination product, brinzolamide 1%/timolol 0.5% (Azarga; Alcon Laboratories, Inc., Fort Worth, TX), has been introduced and received regulatory approval by the European Medicines Agency in November 2008 for the treatment of patients.3 Brinzolamide is a topical carbonic anhydrase inhibitor (CAI) that lowers IOP by decreasing aqueous humor secretion, whereas timolol is a beta-adrenergic blocking agent that reduces IOP by slowing the rate of aqueous humor formation.4,5 In recent studies, the fixed combination of brinzolamide 1% and timolol 0.5% (FCBT) was found to be effective and well tolerated with
1 2
less ocular discomfort and adverse effects.6,7 Adverse effects of topical antiglaucomatous drugs may have undesirable effects on the ocular surface. Ocular surface changes with hypotensive agents have been investigated in many studies.8–10 To our knowledge, there are few studies concerning the effect of FCBT on human cornea. In this study, we aimed to evaluate the short-term effect of FCBT application on central corneal thickness (CCT) of patients who received Nd:YAG laser posterior capsulotomy for posterior capsule opacification (PCO).
Methods This prospective clinical study enrolled 97 patients having Nd:YAG laser posterior capsulotomy for PCO at the Sakarya University Medical Education and Research Hospital Ophthalmology Department between February 2011 and December 2013. Patients were randomized to receive apraclonidine hydrochloride 0.5% (APRA) (n = 48) or FCBT
Sakarya University Medical Education and Research Hospital, Sakarya, Turkey. Department of Ophthalmology, Akdeniz University, Antalya, Turkey.
211
212
(n = 49) at 1 h before laser surgery. Randomization was performed using the order of entrance in the study, with alternate assignment to APRA and FCBT groups. The research followed the tenets of the Declaration of Helsinki, and all patients signed informed consent after they received an explanation of the nature and possible consequences of the procedure. Institutional review board approval was also obtained. Study enrollment comprised consecutive clinic patients. Only 1 eye in each patient was enrolled for study. Patients were excluded if they had previous ocular laser treatment and intraocular surgery except cataract operation. Patients were also excluded if they had a history of corneal disease, use of contact lenses, ocular trauma, use of artificial tears or topical cyclosporine, glaucoma, had active inflammation or infection, had asthma, obstructive pulmonary disease, arrhythmia, renal failure, had known allergy to CAIs or alphaadrenergic agonists, were < 21 years of age, were taking systemic clonidine or topical apraclonidine, and IOP > 21 mmHg before the procedure. All had a history of uneventful phacoemulsification with posterior chamber intraocular lens implantation. All patients had complete baseline eye examinations, including best corrected Snellen visual acuity, slit lamp biomicroscopy, fundus examination, IOP measurement, and CCT measured by ultrasonographic pachymetry (Optikon 2000, Roma, Italy). CCT was evaluated by ultrasonographic pachymetry from the central region after administration of topical proparacaine hydrochloride by the same examiner. The averages of 5 appropriate consecutive readings were taken as the final measurement. The baseline CCT was measured *1 h before the laser procedure. CCT measurements were applied just before the laser application and then the first, second, and third hour, and the first, third, and seventh day after the Nd:YAG laser capsulotomy. The patient and the physician measuring the CCT were unaware of the treatment assignment. To qualify for YAG capsulotomy, the posterior capsule had to be sufficiently opacified causing an objective decrease in best corrected visual acuity. The eyes were dilated with topical tropicamide 1%. Both groups received the drops 1 h before the laser procedure. We used a Q-switched Nd-YAG laser (Laserex SuperQ, Indonesia). All procedures were performed by the same surgeon (G.A.) who was masked to treatment assignment and the drops were given by other researchers. Laser spots were applied until the capsule was opened to *4.0 mm in diameter. The total amount of the laser power and the number of applications were recorded. We initiated the APRA and FCBT drops twice a day for 1 week. In addition to antiglaucomatous drops of FCBT and APRA, patients were prescribed dexamethasone sodium phosphate 0.1% 4 times a day for 1 week. If at any point an unacceptable IOP elevation was observed, the patient would have received other IOP-lowering medication(s) as needed and would have been removed from the study. A postoperative IOP elevation was considered unacceptable if it was thought to be potentially harmful for that patient’s degree of optic nerve cupping or degree of visual field loss. Statistical analysis was performed using SPSS software for Windows version 20 (SPSS, Chicago, IL). The chisquare test was used to compare the demographic and clinical variables between 2 groups. Student’s t test and
CELIK ET AL.
Table 1.
Demographic and Clinical Data of the Groups APRA group
FCBT group
Number of patients 48 49 Sex Male, n (%) 21 (43.8) 26 (53.1) Female, n (%) 27 (56.3) 23 (46.9) Age (years) 67.3 – 10.7 67.3 – 8.3 Surgery-laser interval 55.5 – 26.0 51.6 – 25.0 (months) Total laser energy (mJ) 39 – 22.6 41 – 23.4
P-value 0.419 0.417 0.932 0.196
APRA, apraclonidine hydrochloride 0.5%; FCBT, fixed combination of brinzolamide 1% and timolol 0.5%.
Mann-Whitney U were used to compare the CCT values between the groups. P values < 0.05 were considered as statistically significant.
Results Table 1 shows the demographic and clinical data of the patients. There was no statistically significant difference between the APRA and FCBT groups. The mean IOP before surgery on the day of the procedure was 14.2 – 2.37 mmHg in the APRA group and 13.6 – 2.13 mmHg in the FCBT group (P = 0.062). There was no statistically significant difference between the baseline IOPs of the APRA and FCBT groups. IOP measurements were in normal limits before the procedure and did not differ significantly at control visits. No complication (such as significant intraocular inflammation, intraocular lens damage, hyphema, iris damage, cystoid macular edema, and retinal detachment) was observed after the laser procedure. The mean CCT values of the APRA group at the first, second, and third hour, and the first, third, and seventh day were 553.8 – 28.0, 551.4 – 35.3, 556.8 – 28.7, 552.6 – 27.5, 548.2 – 26.2, and 546.2 – 25.5 mm, respectively. The mean CCT values of the FCBT group at the first, second, and third hour, and the first, third, and seventh day were 544.21 – 34.4, 549.4 – 27.6, 555.94 – 33.1, 550.8 – 33.4, 547.2 – 33.6, and 544.9 – 33.4 mm, respectively. No statistically significant difference was detected between the 2 groups. The CCT raise was observed in both groups after the laser treatment, but on the seventh day, it was subsequently normalized (Table 2). The mean CCT value before the surgery
Table 2. The Mean Central Corneal Thickness Changes from Baseline During Follow-Up Time CCT (mm)
APRA group (n = 48)
FCBT group (n = 49)
P-value
Prelaser 1h 2h 3h 24 h Third day Seventh day
543.8 – 35.5 553.8 – 28.0 551.4 – 35.3 556.8 – 28.7 552.6 – 27.5 548.2 – 26.2 546.2 – 25.5
542.6 – 26.9 544.21 – 34.4 549.4 – 27.6 555.94 – 33.1 550.8 – 33.4 547.2 – 33.6 544.9 – 33.4
0.856 0.882 0.782 0.870 0.829 0.796 0.810
CCT, central corneal thickness.
EFFECT OF BRINZOLAMIDE–TIMOLOL ON CENTRAL CORNEAL THICKNESS
was 543.8 – 35.5 mm in the APRA group. After initiating APRA, the mean CCT values on the first and third day were measured as 552.6 – 27.5 and 548.2 – 26.2 mm, respectively. On the seventh day, the mean CCT values decreased to baseline values. Although there was a minimal thickening of the cornea in the first 3 days, the difference was found to be insignificant (P = 0.16). The mean CCT value before the surgery was 544.21 – 34.4 mm in the FCBT group. After initiating FCBT, the mean CCT values at the first and third day were measured as 552.6 – 27.5 and 548.2 – 26.2 mm, respectively. There was no significant difference before and after the seventh day of surgery (P = 0.22).
Discussion Fixed combinations of IOP-lowering medications provide the efficacy of multiple active agents with the convenience of a 1-bottle regimen. Modern fixed combinations have paired the beta-blocker timolol with various prostaglandin analogs, a CAI, or an adrenergic agonist.11 FCBT is a recently developed effective hypotensive agent comprising the CAI brinzolamide and the beta-blocker timolol. The concentration of brinzolamide is 1% (10 mg/mL), equal to that of brinzolamide ophthalmic suspension (Azopt; Alcon Laboratories, Inc.) and the timolol concentration is 0.5% (5 mg/mL), equal to that of single-agent timolol.12 Safety of FCBT has been demonstrated in several randomized studies. In 2 of the randomized controlled studies, the only systemic adverse event related to FCBT was dysgeusia, a distortion of taste, at an incidence of 3.2% in the ‘‘Manni’s non-inferiority study’’ and 0.8% in the ‘‘Mundorf’s patient preference study.’’1,6 With respect to ocular adverse events, the FCBT group from the Manni study had a significantly lower incidence of ocular irritation and pain. The reason for the superior comfort is likely due to the pH (7.2) of FCBT, which is much closer to physiologic pH. In a recent multicenter study designed by Lanzl and Raber, including 14.025 patients, it was reported that 75.9% of the patients preferred FCBT over the previous treatment, despite the blurred vision problem with FCBT due to its suspension form.13 Adverse effects of topical antiglaucomatous drugs may have an undesirable effect on the ocular surface. Ocular surface changes with hypotensive agents have been investigated in many studies.8–10 As the corneal endothelial carbonic anhydrase has a role in the mechanism of fluid transportation, the use of CAIs may induce changes in the cornea.14–19 Studies are controversial: Wilkerson et al.17 reported that CCT increased in a group using dorzolamide; however, Lass et al.16 did not find any difference in CCT in patients using dorzolamide. In an animal study, dorzolamide was found to have no significant effect on the CCT.14 Wang et al.20 reported no significant CCT changes after 6 weeks of brinzolamide treatment in a group of patients with open angle glaucoma. In a study investigating the effect of short-term brinzolamide application on CCT of patients who received Nd: YAG laser posterior capsulotomy, it was reported that brinzolamide may cause a short-term increase in the human CCT, particularly on the first day and throughout the following week it approximated the baseline values.21 They indicated that brinzolamide has a high inhibitory activity against human carbonic anhydrase II, which is the key isoenzyme regulating aqueous humor production. These
213
properties, along with good ocular bioavailability, make brinzolamide maximally effective in lowering IOP by locally inhibiting carbonic anhydrase II in the ciliary processes and suppressing aqueous humor secretion.4,20 Thus, brinzolamide may interfere with the physiologic function of corneal endothelial cells and may cause a transient increase in the CCT.18,19 The effect of brinzolamide on corneal endothelial cell function has been evaluated by March and Ochsner22 and no meaningful change in endothelial cell density or in CCT was observed between treatment groups. Recently, Firat et al.23 designed a study to evaluate the short-term effect of the FCBT on the ocular surface in glaucoma patients. They examined the subjective symptoms using a questionnaire form of Ocular Surface Disease Index and objective findings with CCT measurements, Schirmer’s I, impression cytology, and tear break-up time (BUT) tests. The results of this study indicated that the short-term use of FCBT does not have a profound effect on ocular surface except BUT values. They observed that CCT values decreased minimally after FCBT therapy, but it was not statistically significant.23 In this study, we examined the short-term effect of FCBT application on CCT of patients who received Nd:YAG laser posterior capsulotomy for PCO. Thus, CCT has been reported as an indicator of corneal endothelial pump and barrier functions; we evaluated the CCT before the laser procedure and at the first, second, and third hour, and the first, third, and seventh day after the Nd:YAG laser capsulotomy. To the best of our knowledge, this is the first study evaluating the short-term effect of FCBT application on CCT of Nd:YAG laser posterior capsulotomy patients. Although CCT is a valid indicator of corneal transparency and health, endothelial cell density measured by specular microscopy reveals additional data and could not be evaluated in this study. This was a limitation of our study. Short-term corneal thickening is an expected condition after laser capsulotomy due to the use of lenses during the procedure, inflammation, and clogging of the trabeculae with debris. We observed that CCT increased initially after the laser procedure in both groups and then started to decrease gradually and approximated the baseline measurements in the following days. However, the difference in CCT increase between both groups was not statistically significant at any follow-up visits. In conclusion, our study revealed that FCBT does not have a short-term effect on CCT. Larger short- and longterm prospective studies should be done to better define the effects of FCBT on human cornea.
Author Disclosure Statement No competing financial interests exist.
References 1. Manni, G., Denis, P., Chew, P., Sharpe, E.D., OrengoNania, S., Coote, M.A., et al. The safety and efficacy of brinzolamide 1%/timolol 0.5% fixed combination versus dorzolamide 2%/timolol 0.5% in patients with open angle glaucoma or ocular hypertension. J. Glaucoma. 18:293– 300, 2009. 2. Kass, M.A., Heuer, D.K., Higginbotham, E.J., Johnson, C.A., Keltner, J.L., Miller, J.P., et al. The Ocular Hypertension Treatment Study: a randomized trial determines
214
3.
4. 5. 6.
7.
8. 9. 10.
11. 12.
13. 14.
CELIK ET AL.
that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch. Ophthalmol. 120:701–713, 2002. Beckers, H.J.M., Schouten, J.S., and Webers, C.A. Role of fixed-combination brinzolamide 1%/timolol 0.5% in the treatment of elevated intraocular pressure in open-angle glaucoma and ocular hypertension. Clin. Ophthalmol. 3: 593–599, 2009. DeSantis, L. Preclinical overview of brinzolamide. Surv. Ophthalmol. 44:119–129, 2004. Reiss, G.R., and Brubaker, R.F. The mechanism of betaxolol, a new ocular hypotensive agent. Ophthalmology. 90:1369–1372, 1983. Mundorf, T.K., Rauchman, S.H., Williams, R.D., and Notivol, R. A patient preference comparison of Azarga (brinzolamide/timolol fixed combination) vs Cosopt (dorzolamide/timolol fixed combination) in patients with open angle-glaucoma or ocular hypertension. Clin. Ophthalmol. 2:623–628, 2008. Vold, S.D., Evans, R.M., Stewart, R.H., Walters, T., and Mallick, S. A one-week comfort study of BID-dosed brinzolamide 1%/timolol 0.5% ophthalmic suspension fixed combination compared to BID-dosed dorzolamide 2%/ timolol 0.5% ophthalmic solution in patients with openangle glaucoma or ocular hypertension. J. Ocul. Pharmacol. Ther. 24:601–605, 2008. Skalicky, S.E., Goldberg, I., and McCluskey P. Ocular surface disease and quality of life in patients with glaucoma. Am. J. Ophthalmol. 153:1–9, 2012. You, J.Y., and Cho, B.J. Effect of latanoprost on central corneal thickness in unilateral normal-tension glaucoma. J. Ocul. Pharmacol. Ther. 29:335–338, 2013. Zhong, Y., Shen, X., Yu, J., Tan, H., and Cheng, Y. The comparison of the effects of latanoprost, travoprost, and bimatoprost on central corneal thickness. Cornea. 30:861– 864, 2011. Fechtner, R.D., and Realini, T. Fixed combinations of topical glaucoma medications. Curr. Opin. Ophthalmol. 15: 132–135, 2004. Kaback, M., Scoper, S.V., Arzeno, G., James, J.E., Hua, S.Y., Salem, C., et al. Intraocular pressure-lowering efficacy of brinzolamide 1%/timolol 0.5% fixed combination compared with brinzolamide 1% and timolol 0.5%. Ophthalmology. 115:1728–1734, 2008. Lanzl, I., and Raber, T. Efficacy and tolerability of the fixed combination of brinzolamide 1% and timolol 0.5% in daily practice. Clin. Ophthalmol. 5:291–298, 2011. Almeida, G.C., and Faria e Souza, S.J. Effect of topical dorzolamide on rabbit central corneal thickness. Braz. J. Med. Biol. Res. 39:277–281, 2006.
15. Wirtitsch, M.G., Findl, O., Kiss, B., Petternel, V., Heinzl, H., and Drexler, W. Short-term effect of dorzolamide hydrochloride on central corneal thickness in humans with cornea guttata. Arch. Ophthalmol. 121:621–625, 2003. 16. Lass, J.H., Khosrof, S.A., Laurence, J.K., Horwitz, B., Ghosh, K., and Adamsons, I. A double-masked, randomized, 1-year study comparing the corneal effects of dorzolamide, timolol, and betaxolol. Dorzolamide Corneal Effects Study Group. Arch. Ophthalmol. 116:1003–1010, 1998. 17. Wilkerson, M., Cyrlin, M., Lippa, E.A., Esposito, D., Deasy, D., Panebianco, D., et al. Four-week safety and efficacy study of dorzolamide, a novel, active topical carbonic anhydrase inhibitor. Arch. Ophthalmol. 111:1343– 1350, 1993. 18. Wu, K.Y., Wang, H.Z., and Hong, S.J. Cellular cytotoxicity of antiglaucoma drugs in cultered corneal endothelial cells. Kaohsiung. J. Med. Sci. 23:105–111, 2007. 19. Zhao, J.C., and Chen, T. Brinzolamide induced reversible corneal decompensation. Br. J. Ophthalmol. 89:389–390, 2005. 20. Wang, T.H., Huang, J.Y., Hung, P.T., Shieh, J.W., and Chen, Y.F. Ocular hypotensive effect and safety of brinzolamide ophthalmic solution in open angle glaucoma patients. J. Formos. Med. Assoc. 103:369–373, 2004. 21. Ornek, K., Gullu, R., Ogurel, T., and Ergin, A. Short-term effect of topical brinzolamide on human central corneal thickness. Eur. J. Ophthalmol. 18:338–340, 2008. 22. March, W.F., and Ochsner, K.I. The long-term safety and efficacy of brinzolamide 1.0% (Azopt) in patients with primary open-angle glaucoma or ocular hypertension. The Brinzolamide Long-Term Therapy Study Group. Am. J. Ophthalmol. 129:136–143, 2000. 23. Firat, P.G., Samdanci, E., Doganay, S., Cavdar, M., Sahin, N., and Gunduz, A. Short-term effect of topical brinzolamidetimolol fixed combination on ocular surface of glaucoma patients. Int. J. Ophthalmol. 5:714–718, 2012.
Received: December 22, 2014 Accepted: January 27, 2015
Address correspondence to: Dr. Elif Betul Turkoglu Department Of Ophthalmology Akdeniz University Antalya 07100 Turkey E-mail: [email protected]
Copyright of Journal of Ocular Pharmacology & Therapeutics is the property of Mary Ann Liebert, Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Short-Term Effect of Topical Brinzolamide 1%–Timolol 0.5% Fixed Combination on Human Central Corneal Thickness Erkan Celik,1 Elif Betul Turkoglu,2 Gonul Altun,1 and Gursoy Alagoz1
Abstract
Purpose: To evaluate the short-term effect of fixed combination of brinzolamide 1% and timolol 0.5% (FCBT) application on human central corneal thickness (CCT). Methods: This prospective clinical study included 97 patients having Nd:YAG laser posterior capsulotomy for posterior capsule opacification. Patients were randomized to receive apraclonidine hydrochloride 0.5% (APRA) (n = 48) or FCBT (n = 49) at 1 h before laser surgery. The baseline CCT was evaluated by ultrasonographic pachymetry from the central region *1 h before the laser procedure. CCT measurements were applied just before the laser application and then the first, second, and third hour, and the first, third, and seventh day after the Nd:YAG laser capsulotomy. Results: There was no statistically significant difference between the baseline intraocular pressures, CCTs, and demographic and clinical data (age, sex, surgery laser interval, total laser energy) of the APRA and the FCBT groups. The mean CCT values of the APRA group at the first, second, and third hour, and the first, third, and seventh day were 553.8 – 28.0, 551.4 – 35.3, 556.8 – 28.7, 552.6 – 27.5, 548.2 – 26.2, and 546.2 – 25.5 mm, respectively. The mean CCT values of the FCBT group at the first, second, and third hour, and the first, third, and seventh day were 544.21 – 34.4, 549.4 – 27.6, 555.94 – 33.1, 550.8 – 33.4, 547.2 – 33.6, and 544.9 – 33.4 mm, respectively. No statistically significant difference was detected between the 2 groups. Conclusion: The difference in CCT increase between both groups was not statistically significant at any followup visits. FCBT application does not have a short-term effect on CCT.
Introduction
T
opical medical therapy is the most common method of intraocular pressure (IOP) reduction, and many topical medications are available for lowering IOP.1 Despite a wide selection of effective single IOP-lowering medications, fixed combinations of topical hypotensive agents are frequently indicated to achieve more IOP reduction.2 Recently, a new fixed combination product, brinzolamide 1%/timolol 0.5% (Azarga; Alcon Laboratories, Inc., Fort Worth, TX), has been introduced and received regulatory approval by the European Medicines Agency in November 2008 for the treatment of patients.3 Brinzolamide is a topical carbonic anhydrase inhibitor (CAI) that lowers IOP by decreasing aqueous humor secretion, whereas timolol is a beta-adrenergic blocking agent that reduces IOP by slowing the rate of aqueous humor formation.4,5 In recent studies, the fixed combination of brinzolamide 1% and timolol 0.5% (FCBT) was found to be effective and well tolerated with
1 2
less ocular discomfort and adverse effects.6,7 Adverse effects of topical antiglaucomatous drugs may have undesirable effects on the ocular surface. Ocular surface changes with hypotensive agents have been investigated in many studies.8–10 To our knowledge, there are few studies concerning the effect of FCBT on human cornea. In this study, we aimed to evaluate the short-term effect of FCBT application on central corneal thickness (CCT) of patients who received Nd:YAG laser posterior capsulotomy for posterior capsule opacification (PCO).
Methods This prospective clinical study enrolled 97 patients having Nd:YAG laser posterior capsulotomy for PCO at the Sakarya University Medical Education and Research Hospital Ophthalmology Department between February 2011 and December 2013. Patients were randomized to receive apraclonidine hydrochloride 0.5% (APRA) (n = 48) or FCBT
Sakarya University Medical Education and Research Hospital, Sakarya, Turkey. Department of Ophthalmology, Akdeniz University, Antalya, Turkey.
211
212
(n = 49) at 1 h before laser surgery. Randomization was performed using the order of entrance in the study, with alternate assignment to APRA and FCBT groups. The research followed the tenets of the Declaration of Helsinki, and all patients signed informed consent after they received an explanation of the nature and possible consequences of the procedure. Institutional review board approval was also obtained. Study enrollment comprised consecutive clinic patients. Only 1 eye in each patient was enrolled for study. Patients were excluded if they had previous ocular laser treatment and intraocular surgery except cataract operation. Patients were also excluded if they had a history of corneal disease, use of contact lenses, ocular trauma, use of artificial tears or topical cyclosporine, glaucoma, had active inflammation or infection, had asthma, obstructive pulmonary disease, arrhythmia, renal failure, had known allergy to CAIs or alphaadrenergic agonists, were < 21 years of age, were taking systemic clonidine or topical apraclonidine, and IOP > 21 mmHg before the procedure. All had a history of uneventful phacoemulsification with posterior chamber intraocular lens implantation. All patients had complete baseline eye examinations, including best corrected Snellen visual acuity, slit lamp biomicroscopy, fundus examination, IOP measurement, and CCT measured by ultrasonographic pachymetry (Optikon 2000, Roma, Italy). CCT was evaluated by ultrasonographic pachymetry from the central region after administration of topical proparacaine hydrochloride by the same examiner. The averages of 5 appropriate consecutive readings were taken as the final measurement. The baseline CCT was measured *1 h before the laser procedure. CCT measurements were applied just before the laser application and then the first, second, and third hour, and the first, third, and seventh day after the Nd:YAG laser capsulotomy. The patient and the physician measuring the CCT were unaware of the treatment assignment. To qualify for YAG capsulotomy, the posterior capsule had to be sufficiently opacified causing an objective decrease in best corrected visual acuity. The eyes were dilated with topical tropicamide 1%. Both groups received the drops 1 h before the laser procedure. We used a Q-switched Nd-YAG laser (Laserex SuperQ, Indonesia). All procedures were performed by the same surgeon (G.A.) who was masked to treatment assignment and the drops were given by other researchers. Laser spots were applied until the capsule was opened to *4.0 mm in diameter. The total amount of the laser power and the number of applications were recorded. We initiated the APRA and FCBT drops twice a day for 1 week. In addition to antiglaucomatous drops of FCBT and APRA, patients were prescribed dexamethasone sodium phosphate 0.1% 4 times a day for 1 week. If at any point an unacceptable IOP elevation was observed, the patient would have received other IOP-lowering medication(s) as needed and would have been removed from the study. A postoperative IOP elevation was considered unacceptable if it was thought to be potentially harmful for that patient’s degree of optic nerve cupping or degree of visual field loss. Statistical analysis was performed using SPSS software for Windows version 20 (SPSS, Chicago, IL). The chisquare test was used to compare the demographic and clinical variables between 2 groups. Student’s t test and
CELIK ET AL.
Table 1.
Demographic and Clinical Data of the Groups APRA group
FCBT group
Number of patients 48 49 Sex Male, n (%) 21 (43.8) 26 (53.1) Female, n (%) 27 (56.3) 23 (46.9) Age (years) 67.3 – 10.7 67.3 – 8.3 Surgery-laser interval 55.5 – 26.0 51.6 – 25.0 (months) Total laser energy (mJ) 39 – 22.6 41 – 23.4
P-value 0.419 0.417 0.932 0.196
APRA, apraclonidine hydrochloride 0.5%; FCBT, fixed combination of brinzolamide 1% and timolol 0.5%.
Mann-Whitney U were used to compare the CCT values between the groups. P values < 0.05 were considered as statistically significant.
Results Table 1 shows the demographic and clinical data of the patients. There was no statistically significant difference between the APRA and FCBT groups. The mean IOP before surgery on the day of the procedure was 14.2 – 2.37 mmHg in the APRA group and 13.6 – 2.13 mmHg in the FCBT group (P = 0.062). There was no statistically significant difference between the baseline IOPs of the APRA and FCBT groups. IOP measurements were in normal limits before the procedure and did not differ significantly at control visits. No complication (such as significant intraocular inflammation, intraocular lens damage, hyphema, iris damage, cystoid macular edema, and retinal detachment) was observed after the laser procedure. The mean CCT values of the APRA group at the first, second, and third hour, and the first, third, and seventh day were 553.8 – 28.0, 551.4 – 35.3, 556.8 – 28.7, 552.6 – 27.5, 548.2 – 26.2, and 546.2 – 25.5 mm, respectively. The mean CCT values of the FCBT group at the first, second, and third hour, and the first, third, and seventh day were 544.21 – 34.4, 549.4 – 27.6, 555.94 – 33.1, 550.8 – 33.4, 547.2 – 33.6, and 544.9 – 33.4 mm, respectively. No statistically significant difference was detected between the 2 groups. The CCT raise was observed in both groups after the laser treatment, but on the seventh day, it was subsequently normalized (Table 2). The mean CCT value before the surgery
Table 2. The Mean Central Corneal Thickness Changes from Baseline During Follow-Up Time CCT (mm)
APRA group (n = 48)
FCBT group (n = 49)
P-value
Prelaser 1h 2h 3h 24 h Third day Seventh day
543.8 – 35.5 553.8 – 28.0 551.4 – 35.3 556.8 – 28.7 552.6 – 27.5 548.2 – 26.2 546.2 – 25.5
542.6 – 26.9 544.21 – 34.4 549.4 – 27.6 555.94 – 33.1 550.8 – 33.4 547.2 – 33.6 544.9 – 33.4
0.856 0.882 0.782 0.870 0.829 0.796 0.810
CCT, central corneal thickness.
EFFECT OF BRINZOLAMIDE–TIMOLOL ON CENTRAL CORNEAL THICKNESS
was 543.8 – 35.5 mm in the APRA group. After initiating APRA, the mean CCT values on the first and third day were measured as 552.6 – 27.5 and 548.2 – 26.2 mm, respectively. On the seventh day, the mean CCT values decreased to baseline values. Although there was a minimal thickening of the cornea in the first 3 days, the difference was found to be insignificant (P = 0.16). The mean CCT value before the surgery was 544.21 – 34.4 mm in the FCBT group. After initiating FCBT, the mean CCT values at the first and third day were measured as 552.6 – 27.5 and 548.2 – 26.2 mm, respectively. There was no significant difference before and after the seventh day of surgery (P = 0.22).
Discussion Fixed combinations of IOP-lowering medications provide the efficacy of multiple active agents with the convenience of a 1-bottle regimen. Modern fixed combinations have paired the beta-blocker timolol with various prostaglandin analogs, a CAI, or an adrenergic agonist.11 FCBT is a recently developed effective hypotensive agent comprising the CAI brinzolamide and the beta-blocker timolol. The concentration of brinzolamide is 1% (10 mg/mL), equal to that of brinzolamide ophthalmic suspension (Azopt; Alcon Laboratories, Inc.) and the timolol concentration is 0.5% (5 mg/mL), equal to that of single-agent timolol.12 Safety of FCBT has been demonstrated in several randomized studies. In 2 of the randomized controlled studies, the only systemic adverse event related to FCBT was dysgeusia, a distortion of taste, at an incidence of 3.2% in the ‘‘Manni’s non-inferiority study’’ and 0.8% in the ‘‘Mundorf’s patient preference study.’’1,6 With respect to ocular adverse events, the FCBT group from the Manni study had a significantly lower incidence of ocular irritation and pain. The reason for the superior comfort is likely due to the pH (7.2) of FCBT, which is much closer to physiologic pH. In a recent multicenter study designed by Lanzl and Raber, including 14.025 patients, it was reported that 75.9% of the patients preferred FCBT over the previous treatment, despite the blurred vision problem with FCBT due to its suspension form.13 Adverse effects of topical antiglaucomatous drugs may have an undesirable effect on the ocular surface. Ocular surface changes with hypotensive agents have been investigated in many studies.8–10 As the corneal endothelial carbonic anhydrase has a role in the mechanism of fluid transportation, the use of CAIs may induce changes in the cornea.14–19 Studies are controversial: Wilkerson et al.17 reported that CCT increased in a group using dorzolamide; however, Lass et al.16 did not find any difference in CCT in patients using dorzolamide. In an animal study, dorzolamide was found to have no significant effect on the CCT.14 Wang et al.20 reported no significant CCT changes after 6 weeks of brinzolamide treatment in a group of patients with open angle glaucoma. In a study investigating the effect of short-term brinzolamide application on CCT of patients who received Nd: YAG laser posterior capsulotomy, it was reported that brinzolamide may cause a short-term increase in the human CCT, particularly on the first day and throughout the following week it approximated the baseline values.21 They indicated that brinzolamide has a high inhibitory activity against human carbonic anhydrase II, which is the key isoenzyme regulating aqueous humor production. These
213
properties, along with good ocular bioavailability, make brinzolamide maximally effective in lowering IOP by locally inhibiting carbonic anhydrase II in the ciliary processes and suppressing aqueous humor secretion.4,20 Thus, brinzolamide may interfere with the physiologic function of corneal endothelial cells and may cause a transient increase in the CCT.18,19 The effect of brinzolamide on corneal endothelial cell function has been evaluated by March and Ochsner22 and no meaningful change in endothelial cell density or in CCT was observed between treatment groups. Recently, Firat et al.23 designed a study to evaluate the short-term effect of the FCBT on the ocular surface in glaucoma patients. They examined the subjective symptoms using a questionnaire form of Ocular Surface Disease Index and objective findings with CCT measurements, Schirmer’s I, impression cytology, and tear break-up time (BUT) tests. The results of this study indicated that the short-term use of FCBT does not have a profound effect on ocular surface except BUT values. They observed that CCT values decreased minimally after FCBT therapy, but it was not statistically significant.23 In this study, we examined the short-term effect of FCBT application on CCT of patients who received Nd:YAG laser posterior capsulotomy for PCO. Thus, CCT has been reported as an indicator of corneal endothelial pump and barrier functions; we evaluated the CCT before the laser procedure and at the first, second, and third hour, and the first, third, and seventh day after the Nd:YAG laser capsulotomy. To the best of our knowledge, this is the first study evaluating the short-term effect of FCBT application on CCT of Nd:YAG laser posterior capsulotomy patients. Although CCT is a valid indicator of corneal transparency and health, endothelial cell density measured by specular microscopy reveals additional data and could not be evaluated in this study. This was a limitation of our study. Short-term corneal thickening is an expected condition after laser capsulotomy due to the use of lenses during the procedure, inflammation, and clogging of the trabeculae with debris. We observed that CCT increased initially after the laser procedure in both groups and then started to decrease gradually and approximated the baseline measurements in the following days. However, the difference in CCT increase between both groups was not statistically significant at any follow-up visits. In conclusion, our study revealed that FCBT does not have a short-term effect on CCT. Larger short- and longterm prospective studies should be done to better define the effects of FCBT on human cornea.
Author Disclosure Statement No competing financial interests exist.
References 1. Manni, G., Denis, P., Chew, P., Sharpe, E.D., OrengoNania, S., Coote, M.A., et al. The safety and efficacy of brinzolamide 1%/timolol 0.5% fixed combination versus dorzolamide 2%/timolol 0.5% in patients with open angle glaucoma or ocular hypertension. J. Glaucoma. 18:293– 300, 2009. 2. Kass, M.A., Heuer, D.K., Higginbotham, E.J., Johnson, C.A., Keltner, J.L., Miller, J.P., et al. The Ocular Hypertension Treatment Study: a randomized trial determines
214
3.
4. 5. 6.
7.
8. 9. 10.
11. 12.
13. 14.
CELIK ET AL.
that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch. Ophthalmol. 120:701–713, 2002. Beckers, H.J.M., Schouten, J.S., and Webers, C.A. Role of fixed-combination brinzolamide 1%/timolol 0.5% in the treatment of elevated intraocular pressure in open-angle glaucoma and ocular hypertension. Clin. Ophthalmol. 3: 593–599, 2009. DeSantis, L. Preclinical overview of brinzolamide. Surv. Ophthalmol. 44:119–129, 2004. Reiss, G.R., and Brubaker, R.F. The mechanism of betaxolol, a new ocular hypotensive agent. Ophthalmology. 90:1369–1372, 1983. Mundorf, T.K., Rauchman, S.H., Williams, R.D., and Notivol, R. A patient preference comparison of Azarga (brinzolamide/timolol fixed combination) vs Cosopt (dorzolamide/timolol fixed combination) in patients with open angle-glaucoma or ocular hypertension. Clin. Ophthalmol. 2:623–628, 2008. Vold, S.D., Evans, R.M., Stewart, R.H., Walters, T., and Mallick, S. A one-week comfort study of BID-dosed brinzolamide 1%/timolol 0.5% ophthalmic suspension fixed combination compared to BID-dosed dorzolamide 2%/ timolol 0.5% ophthalmic solution in patients with openangle glaucoma or ocular hypertension. J. Ocul. Pharmacol. Ther. 24:601–605, 2008. Skalicky, S.E., Goldberg, I., and McCluskey P. Ocular surface disease and quality of life in patients with glaucoma. Am. J. Ophthalmol. 153:1–9, 2012. You, J.Y., and Cho, B.J. Effect of latanoprost on central corneal thickness in unilateral normal-tension glaucoma. J. Ocul. Pharmacol. Ther. 29:335–338, 2013. Zhong, Y., Shen, X., Yu, J., Tan, H., and Cheng, Y. The comparison of the effects of latanoprost, travoprost, and bimatoprost on central corneal thickness. Cornea. 30:861– 864, 2011. Fechtner, R.D., and Realini, T. Fixed combinations of topical glaucoma medications. Curr. Opin. Ophthalmol. 15: 132–135, 2004. Kaback, M., Scoper, S.V., Arzeno, G., James, J.E., Hua, S.Y., Salem, C., et al. Intraocular pressure-lowering efficacy of brinzolamide 1%/timolol 0.5% fixed combination compared with brinzolamide 1% and timolol 0.5%. Ophthalmology. 115:1728–1734, 2008. Lanzl, I., and Raber, T. Efficacy and tolerability of the fixed combination of brinzolamide 1% and timolol 0.5% in daily practice. Clin. Ophthalmol. 5:291–298, 2011. Almeida, G.C., and Faria e Souza, S.J. Effect of topical dorzolamide on rabbit central corneal thickness. Braz. J. Med. Biol. Res. 39:277–281, 2006.
15. Wirtitsch, M.G., Findl, O., Kiss, B., Petternel, V., Heinzl, H., and Drexler, W. Short-term effect of dorzolamide hydrochloride on central corneal thickness in humans with cornea guttata. Arch. Ophthalmol. 121:621–625, 2003. 16. Lass, J.H., Khosrof, S.A., Laurence, J.K., Horwitz, B., Ghosh, K., and Adamsons, I. A double-masked, randomized, 1-year study comparing the corneal effects of dorzolamide, timolol, and betaxolol. Dorzolamide Corneal Effects Study Group. Arch. Ophthalmol. 116:1003–1010, 1998. 17. Wilkerson, M., Cyrlin, M., Lippa, E.A., Esposito, D., Deasy, D., Panebianco, D., et al. Four-week safety and efficacy study of dorzolamide, a novel, active topical carbonic anhydrase inhibitor. Arch. Ophthalmol. 111:1343– 1350, 1993. 18. Wu, K.Y., Wang, H.Z., and Hong, S.J. Cellular cytotoxicity of antiglaucoma drugs in cultered corneal endothelial cells. Kaohsiung. J. Med. Sci. 23:105–111, 2007. 19. Zhao, J.C., and Chen, T. Brinzolamide induced reversible corneal decompensation. Br. J. Ophthalmol. 89:389–390, 2005. 20. Wang, T.H., Huang, J.Y., Hung, P.T., Shieh, J.W., and Chen, Y.F. Ocular hypotensive effect and safety of brinzolamide ophthalmic solution in open angle glaucoma patients. J. Formos. Med. Assoc. 103:369–373, 2004. 21. Ornek, K., Gullu, R., Ogurel, T., and Ergin, A. Short-term effect of topical brinzolamide on human central corneal thickness. Eur. J. Ophthalmol. 18:338–340, 2008. 22. March, W.F., and Ochsner, K.I. The long-term safety and efficacy of brinzolamide 1.0% (Azopt) in patients with primary open-angle glaucoma or ocular hypertension. The Brinzolamide Long-Term Therapy Study Group. Am. J. Ophthalmol. 129:136–143, 2000. 23. Firat, P.G., Samdanci, E., Doganay, S., Cavdar, M., Sahin, N., and Gunduz, A. Short-term effect of topical brinzolamidetimolol fixed combination on ocular surface of glaucoma patients. Int. J. Ophthalmol. 5:714–718, 2012.
Received: December 22, 2014 Accepted: January 27, 2015
Address correspondence to: Dr. Elif Betul Turkoglu Department Of Ophthalmology Akdeniz University Antalya 07100 Turkey E-mail: [email protected]
Copyright of Journal of Ocular Pharmacology & Therapeutics is the property of Mary Ann Liebert, Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
