Abstract
Purpose
The purpose of the study was to compare the systemic safety and risk–benefit ratio of 0.1% timolol hydrogel and 0.5% aqueous timolol eye drops in the treatment of glaucoma.
Methods
An 8-week randomised, double-blind, cross-over, multicentre study. A total of 25 patients with primary open-angle glaucoma, exfoliation glaucoma, or ocular hypertension was enrolled. After completing a wash-out period, patients were randomly chosen to receive either 0.1% timolol hydrogel once daily or 0.5% aqueous timolol eye drops twice daily. Intraocular pressure and heart rate during rest and exercise, head-up tilt test results, spirometry readings, and plasma concentrations of timolol were recorded. The risk–benefit ratio was determined by calculating the ratio between several heart rate endpoints and the change in intraocular pressure (IOP).
Results
The mean drug-induced change in the peak heart rate during exercise was −13.5 beats/min (SD 7.6) in the 0.5% aqueous timolol group and −5.1 beats/min (SD 6.7) in the 0.1% timolol hydrogel group (P<0.001; 95% CI 4.06–12.18). There was no significant difference in the IOP-reducing efficacy between these compounds. The risk–benefit ratio was significantly improved when 0.1% timolol hydrogel was used, compared with 0.5% aqueous timolol in the exercise test. In the head-up tilt test the risk–benefit ratio was significantly improved at rest (P<0.05), at 1 min (P<0.05) and at 5 min (P<0.001) after patients had received 0.1% timolol hydrogel. There were, however, no differences in spirometry readings. After patients had been treated with 0.1% timolol hydrogel, plasma concentrations of timolol were 1/6 (at peak) and 1/50 (at trough) of those of 0.5% aqueous timolol.
Conclusions
Drug-induced changes in the peak heart rate, and head-up tilt test results as well as plasma concentrations of timolol, were significantly more pronounced after treatment with 0.5% aqueous timolol than with 0.1% timolol hydrogel. Because of the statistically similar IOP-reducing efficacy of these formulations the risk–benefit ratio was significantly improved when patients used 0.1% timolol hydrogel instead of 0.5% aqueous timolol.
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References
Boger WP III (1979) Timolol: short term “escape” and long term “drift”. Ann Ophthalmol 11:1239–1242
Brooks AM, Gillies WE (1992) Ocular beta-blockers in glaucoma management. Clinical pharmacological aspects. Drugs Aging 2:208–221
Dickstein K, Aarsland T (1996) Comparison of the effects of aqueous and gellan ophthalmic timolol on peak exercise performance in middle-aged men. Am J Ophthalmol 121:367–371
Dickstein K, Hapnes R, Aarsland T (2001) Comparison of aqueous and gellan ophthalmic timolol with placebo on the 24-hour heart rate response in patients on treatment for glaucoma. Am J Ophthalmol 132:626–631
Everitt DE, Avorn J (1990) Systemic effects of medications used to treat glaucoma. Ann Int Med 112:120–125
Frishman WH, Kowalski M, Nagnur S, Warshafsky S, Sica D (2001) Cardiovascular considerations in using topical, oral, and intravenous drugs for the treatment of glaucoma and ocular hypertension: focus on beta-adrenergic blockade. Heart Dis 3:386–397
Hayreh SS, Podhajsky P, Zimmerman MB (1999) Beta-blocker eyedrops and nocturnal arterial hypotension. Am J Ophthalmol 128:301–309
Heel RC, Brodgen RN, Speight TM, Avery GS (1979) Timolol: a review of its therapeutic efficacy in the topical treatment of glaucoma. Drugs 17:38–55
Mayer H, von der Ohe N (1996) Efficacy of a novel hydrogel formulation in human volunteers. Ophthalmologica 210:101–103
Nelson WL, Fraunfelder FT, Sills JM, Arrowsmith JB, Kuritsky JN (1985) Adverse respiratory and cardiovascular events attributed to timolol ophthalmic solution, 1978–1985. Am J Ophthalmol 102:606–611
Niño J, Tahvanainen K, Uusitalo H, Turjanmaa V, Hutri-Kähönen N, Kaila T, Ropo A, Kuusela T, Kähönen M (2002) Cardiovascular effects of ophthalmic 0.5% timolol aqueous solution and 0.1% timolol hydrogel. Clin Physiol Funct Imaging 22:271–278
Rouland JF, Morel-Mandrino P, Elena PP, Polzer H, Sunder Raj P (2002) Timolol 0.1% gel (Nyogel 0.1%) once daily versus conventional timolol 0.5% solution twice daily: a comparison of efficacy and safety. Ophthalmologica 216:449–454
Silverstone D, Zimmerman T, Choplin N, Mundorf T, Rose A, Stoecker J, Kelley E, Lue J (1991) Evaluation of once-daily levobunolol 0.25% and timolol 0.25% therapy for increased intraocular pressure. Am J Ophthalmol 112:56–60
Thylefors B, Négrel AD, Pararajasegaram R, Dadzie KY (1995) Global data on blindness. Bull World Health Organ 73:115–121
Uusitalo H, Niño J, Tahvanainen K, Turjanmaa V, Ropo A, Tuominen J, Kähönen M (2005) Efficacy and systemic side effects of topical 0.5% timolol aqueous solution and 0.1% timolol hydrogel. Acta Ophthalmol Scand 83:723–728
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The study was supported by Santen Oy, Tampere, Finland. H. Uusitalo, G. Bjärnhall and H. Hedenström received financial support from Santen Oy. A. Ropo and J. Mäenpää are employees of Santen Oy. V. Turjanmaa and M. Kähönen have no financial relationship with Santen Oy.
The authors have full control of all primary data and they agree to allow Graefe’s Archive for Clinical and Experimental Ophthalmology to review their data if requested.
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Uusitalo, H., Kähönen, M., Ropo, A. et al. Improved systemic safety and risk–benefit ratio of topical 0.1% timolol hydrogel compared with 0.5% timolol aqueous solution in the treatment of glaucoma. Graefe's Arch Clin Exp Ophthalmo 244, 1491–1496 (2006). https://doi.org/10.1007/s00417-006-0328-0
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DOI: https://doi.org/10.1007/s00417-006-0328-0