Diurnal and Nocturnal Variations in Aqueous Humor Dynamics of Patients With Ocular Hypertension Undergoing Medical Therapy
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Abstract:
To evaluate the interaction of intraocular pressure(IOP)–lowering medications with physiologic day and night changes in aqueous humor dynamics in participants with ocular hypertension.Thirty participants were enrolled in thisdouble-masked, randomized, crossover study. Each participant underwent aqueous humor dynamics measurements at baseline and at 2 weeks of dosing in random order with latanoprost in the evening and placebo in the morning, timolol maleate twice daily, and dorzolamide hydrochloride twice daily. Measurements included central corneal thickness by ultrasound pachymetry, anterior chamber depth by A-scan, seated and habitual IOP by pneumatonometry, blood pressure by sphygmomanometry,episcleral venous pressure by venomanometry,and aqueous flow by fluorophotometry. Outflow facility was assessed by fluorophotometry and by tonography. Uveoscleral outflow was mathematically calculated using the Goldmann equation.Latanoprost use significantly decreased IOP during the day and night. It increased daytime uveoscleral outflow by a mean (SD) of 0.90 (1.46) μL/min (P=.048), but a nighttime increase of 0.26 (1.10) μL/min (P=.47)did not reach statistical significance. Timolol use decreased IOP during the day by reducing aqueous flow by 25%. Dorzolamide use lowered IOP only at the noon measurement and reduced daytime aqueous flow by 16%. Neither dorzolamide nor timolol use added to the physiologic 47% reduction in nighttime aqueous flow.The daytime IOP-lowering effects of latanoprost are mediated by an increase in uveoscleral outflow,and those of timolol and dorzolamide are mediated by aqueous flow suppression. Nighttime physiologic changes in uveoscleral outflow limit the nighttime pharmacodynamic efficacy of latanoprost. Aqueous flow suppression with timolol and dorzolamide was ineffective in obtaining IOP lowering at night.Keywords:
Dorzolamide
Crossover study
(1) First-line drug treatment of chronic open-angle glaucoma or intraocular hypertonia is based on monotherapy with timolol eye drops. Patients in whom several single-agent treatments have failed can use combinations of timolol + dorzolamide (a carbonic anhydrase inhibitor) or a betablocker + pilocarpine (a parasympathomimetic agent). (2) An eye-drop preparation is now available in which 0.5% timolol is combined with 0.005% latanoprost, a prostaglandin F2alpha analogue. (3) A clinical trial indicated that the timolol + latanoprost combination was more effective than the timolol + dorzolamide combination on intraocular pressure, but the report of this study is too scanty to accept these results at face value. Once-a-day dosing with timolol + latanoprost has not been compared with a betablocker + pilocarpine combination. (4) Patients using the timolol + latanoprost combination are exposed to the adverse effects of both latanoprost (especially ocular irritation and brown iris discoloration) and the betablocker. (5) It is not known whether the once-a-day dosing of the timolol + latanoprost combination is a significant advantage, especially in terms of adherence to treatment. (6) In practice, the arrival of the timolol + latanoprost combination changes virtually nothing for patients with chronic open-angle glaucoma, except for those with no other alternative.
Dorzolamide
Pilocarpine
Carbonic anhydrase inhibitor
Travoprost
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Objective: The aim of this study was to evaluate the efficacy and tolerability of latanoprost, compared with the combination of dorzolamide and timolol, in the treatment of patients with elevated intraocular pressure (IOP). Methods: Pertinent randomized, controlled trials were identified through systematic searches of the Cochrane Library, PubMed, EMBASE, Chinese Biomedicine Database, and internet searches of meeting abstracts and the manufacturers' databases. The main efficacy measures were the IOP reduction (IOPR), including diurnal mean IOPR, and 10:00 IOPR. The main tolerability measure was withdrawal due to adverse events and individual adverse events. Results: Fourteen (14) studies involving 2149 patients were included in the meta-analysis. Latanoprost was significantly more effective in lowering diurnal mean IOP than combined dorzolamide and timolol in patients with IOP insufficiently controlled by timolol alone, with a weighted mean difference (WMD) for the diurnal mean IOPR% of 3.12 (95% confidence interval, 0.47–5.78) at 3 months, and latanoprost was as effective as the combination of dorzolamide and timolol in patients without baseline timolol treatment. The combination of dorzolamide and timolol was associated with numerically greater reductions in 10:00 IOP, compared with latanoprost in patients with or without timolol treatment at baseline: only the result in patients with baseline timolol treatment at 1 month was statistically significant (WMD −4.14: range, −5.78 to −2.50). The combination of dorzolamide and timolol was less tolerated than latanoprost, with pooled relative risk for withdrawals due to adverse events being 0.34 (range, 0.13–0.84). Conclusions: Latanoprost was associated with significantly greater efficacy in lowering diurnal mean IOP than combined dorzolamide and timolol in patients with IOP insufficiently controlled by timolol alone, and latanoprost was as effective as combined dorzolamide and timolol in patients without baseline timolol treatment. The combination of dorzolamide and timolol was less tolerated than latanoprost.
Dorzolamide
Tolerability
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Purpose: To investigate the corneal toxicity of three combined antiglaucoma topical eyedrops using transepithelial electrical resistance (TER) and scanning electron microscopy (SEM).Methods: Corneal TER changes after a 60-s exposure to latanoprost/timolol with 0.02% benzalkonium chloride (BAC), travoprost/timolol with polyquaternium-1, and dorzolamide/timolol with 0.005% BAC were measured in living rabbits. Corneal damage was also examined by SEM. Hank’s balanced salt solution (HBSS) was used as a control.Results: There was a significant decrease in the corneal TER after exposure of the cornea to latanoprost/timolol with 0.02% BAC. Travoprost/timolol with polyquaternium-1 and dorzolamide/timolol with 0.005% BAC did not produce any significant decrease in the corneal TER as compared to HBSS control eyes. SEM revealed that superficial cells of corneas treated with latanoprost/timolol with 0.02% BAC were damaged and exhibited degenerated microvilli. Conversely, the superficial cells of corneas exposed to travoprost/timolol with polyquaternium-1 or dorzolamide/timolol with 0.005% BAC appeared normal and had normal microvilli under SEM examinations.Conclusion: The corneal toxicity of latanoprost/timolol with 0.02% BAC is greater than that of travoprost/timolol with polyquaternium-1 and dorzolamide/timolol with 0.005% BAC. Latanoprost/timolol contains 0.02% BAC, which may be responsible for the corneal toxicity.
Travoprost
Dorzolamide
Benzalkonium chloride
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Dorzolamide
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Dorzolamide
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Purpose: The aim of this study was to evaluate the efficacy and safety in ocular hypertensive or open-angle glaucoma patients changed to a latanoprost/timolol fixed combination (LTFC) from previous therapy. Methods: We employed a retrospective, multicenter, active-controlled study evaluating patients who had a previous therapy substituted with LTFC and had a 3-month follow-up. Results: In the 168 patients included in the trial, LTFC reduced the intraocular pressure (IOP) after switching from previous therapies: timolol (22.8 ± 3.5 to 19.0 ± 3.9 mmHg, N = 49, p < 0.001), latanoprost (21.2 ± 3.8 to 18.3 ± 2.5 mmHg, N = 54, p < 0.001), and a dorzolamide/timolol fixed combination (20.9 ± 2.4 to 20.0 ± 2.7 mmHg, N = 32, p = 0.03). In switching from a latanoprost and timolol unfixed combination, the pressure changed from 18.3 ± 3.8 to 18.9 ± 3.0 mmHg (N = 33, p = 0.38). LTFC was persistent in 131 (78%) patients within the 3-month treatment period. The most common adverse event with LTFC was conjunctival hyperemia, which occurred in patients not previously treated with latanoprost therapy (N = 16, 10%). Conclusions: LTFC generally provides reduced IOP and limited side effects when substituted for other common glaucoma therapies, while providing similar pressure when switched from its own individual components.
Dorzolamide
Combination therapy
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The purpose of this study was to evaluate the efficacy and safety of two fixed combinations, ie, timolol 0.5% + brimonidine 0.2% + dorzolamide 2% (TBD) versus timolol 0.5% + brimonidine 0.2% (TB) in patients with primary open-angle glaucoma or ocular hypertension.We performed a 3-month, randomized, double-blind study in patients with primary open-angle glaucoma or ocular hypertension and an intraocular pressure of 21-30 mmHg. Patients were randomly assigned to receive one drop of TBD or TB twice a day. The primary efficacy endpoint was change in intraocular pressure after 3 months of treatment. Safety measures were assessed by the presence of adverse events.Mean baseline intraocular pressure was similar at 8 am and 4 pm in the treatment groups (TBD 22.3 ± 0.9 mmHg, TB 22.4 ± 1.8 mmHg, P = 0.558; TBD 19.02 ± 1.3, TB 19.08 ± 1.2, P = 0.536, respectively). At the end of the study, the mean intraocular pressure was significantly lower in the TBD group at both 8 am (16.19 ± 2.0 mmHg versus 18.35 ± 1.4 mmHg, P = 0.000) and 4 pm (14.74 ± 2.4 mmHg versus 16.77 ± 1.4 mmHg, P = 0.000).Fixed-combination TBD was more effective than fixed-combination TB for reducing IOP in patients with primary open-angle glaucoma.
Brimonidine
Dorzolamide
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Purpose: The purpose of this study is to compare the efficacy and safety of 2% long-acting carteolol solution with 0.5% timolol gel-forming solution added to primary treatment of 0.005% latanoprost solution in patients with primary open-angle glaucoma and ocular hypertension. Materials and Methods: After at least 4 weeks primary treatment with latanoprost, all patients received the combination therapy with either 2% long-acting carteolol or 0.5% timolol gel in addition to latanoprost for 8 weeks. We measured intraocular pressure (IOP) and evaluated systemic and local adverse events between Day 1 and Day 56. Results: Carteolol significantly reduced the IOP from baseline (latanoprost monotherapy) by 11.0% at Day 28 and 11.2% at Day 56. Timolol also reduced IOP by 11.5% at Day 28 and 11.0% at Day 56. There was no statistically significant difference in the IOP reduction between the two groups. There was no adverse event related to the administration of these anti-glaucoma medications during the study period. Conclusions: Both once daily carteolol and timolol medications are safe and effective treatments combined with latanoprost single therapy.
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