Combined therapy of pilocarpine or latanoprost with timolol versus latanoprost monotherapy

Adjunctive intraocular pressure (IOP)-lowering therapy is widely used today, as one-third of all patients being treated for glaucoma need additional therapy to reach and maintain healthy IOPs. Timolol, latanoprost, and pilocarpine are three potent drugs that have been used in combination to reduce IOP. Timolol reduces the production rate of aqueous humor to achieve the IOP decrease. Latanoprost and pilocarpine both affect aqueous outflow, although by different mechanisms. The IOP efficacy of combined therapy with timolol and pilocarpine compared with timolol and latanoprost or with latanoprost alone has been investigated in three multicenter, randomized, clinical trials in Europe. This is a review of those published trials. In 2 of the 3 studies, the additional IOP lowering effect of latanoprost 0.005% administered once daily was compared with pilocarpine 2% administered 3 times daily in patients with primary open-angle glaucoma (POAG) or ocular hypertension currently on monotherapy with timolol 0.5% twice daily. These 6-month studies found that the timolol and latanoprost combination reduced IOP more and was better tolerated with fewer side-effects than the timolol and pilocarpine combination. At 6 months, there was no evidence of long-term drift in IOP with timolol and latanoprost. This combined therapy provides an effective and safe option for lowering IOP in glaucoma patients. These results suggest that the timolol/latanoprost combination is preferable to the timolol/pilocarpine combination not only with regard to side effects but also to the magnitude of IOP reduction. Two of the 3 studies compared latanoprost monotherapy with timolol and pilocarpine combined therapy in patients with POAG, various other glaucomas, or ocular hypertension. Treatment was for 6 weeks or 6 months. In both studies, latanoprost was more effective and better tolerated than the combination of timolol and pilocarpine. These results suggest that latanoprost alone should be tried before the addition of pilocarpine to timolol therapy is considered. The convenience of daily administration of a single drop of latanoprost versus multiple drops of timolol and pilocarpine should improve patient compliance.     

Efficacy and safety of timolol solution once daily vs timolol gel added to latanoprost

PURPOSE: To compare the efficacy and safety of timolol hemihydrate 0.5% (Betimol, Ciba Vision Ophthalmics, Duluth, Georgia) vs timolol maleate gel-forming solution 0.5% (Timoptic-XE, Merck, Blue Bell, Pennsylvania), both given every morning added to latanoprost 0.005% given every evening. METHODS: A multicenter, randomized, crossover comparison was performed in patients with primary open-angle glaucoma or ocular hypertension. After at least a 4-week run-in period with latanoprost 0.005% (Xalatan, Pharmacia & Upjohn, Kalamazoo, Michigan), both eyes from 30 patients (60 eyes) were randomly assigned to one of the two adjunctive therapies, timolol hemihydrate or timolol maleate gel for 6 weeks. At the end of the first period, the study medicine was discontinued for a 2-week washout period. Patients then received the opposite medication for the second 6-week period. This study had an 80% power to exclude a 1-mm Hg difference between groups. RESULTS: The baseline intraocular pressure after 1 month of latanoprost treatment only for all 30 subjects was 20.8 +/- 2.6 mm Hg. After 6 weeks of timolol hemihydrate, the 24-hour trough intraocular pressure was 17.5 +/- 3.4 mm Hg, and for timolol maleate gel, 17.9 +/- 3.5 mm Hg (P = .74). The peak level 2 hours after dosing for timolol hemihydate was 16.4 +/- 2.6 mm Hg, and for timolol maleate gel, 16.8 +/- 3.8 mm Hg (P = .84). No patient was discontinued from the study because of lack of efficacy. No differences were observed between treatments in visual acuity, anterior segment findings, or adverse events. CONCLUSIONS: Once-daily beta-blocker therapy is an effective ocular hypotensive adjunctive treatment 24 hours after dosing when added to latanoprost, for which timolol hemihydrate 0.5% solution and timolol maleate gel 0.5% appear equally effective and safe.     

Randomized crossover study of latanoprost and travoprost in eyes with open-angle glaucoma

Introduction  

To compare the intraocular pressure (IOP)-lowering effects of 0.005% latanoprost to that of 0.004% travoprost in eyes with open-angle glaucoma (OAG).     

Predicting intraocular pressure change before initiating therapy: timolol versus latanoprost

Purpose: To study intraocular pressure (IOP) reductions with timolol and latanoprost reached in clinical practice, taking into account data that are routinely collected by the ophthalmologist; to predict IOP reduction from these variables. Methods: A cohort of patients with primary open‐angle glaucoma (suspect) or ocular hypertension was recruited from nine Dutch centres. Mean absolute and relative IOP reduction was calculated in order to compare timolol to latanoprost. IOP reduction was calculated by comparing patients with certain characteristics to those who had none. Results: One hundred and fifty‐six persons started on timolol and 76 started on latanoprost monotherapy. Mean [95% confidence interval (CI)] absolute reduction was 7.2 mmHg (7.9; 6.5) for timolol and 6.9 mmHg (8.0; 5.8) for latanoprost. Mean relative reduction (95% CI) was 27.2% (29.3; 25.1) for timolol and 26.6% (30.2; 22.9) for latanoprost. No significant difference in IOP reduction between timolol and latanoprost was found when adjusting for data that are routinely collected by the ophthalmologist. At the time of starting treatment, none of these items normally used for the management of glaucoma, except IOP at baseline, could predict change in IOP. Conclusion: In clinical practice, timolol and latanoprost achieve similar IOP reductions that are comparable to those achieved in randomized trials. No clinically relevant information for glaucoma management can be used to predict IOP reduction accurately.     

Additive effect of latanoprost to the combination of timolol and dorzolamide

PURPOSE: To study the additive effect of latanoprost 0.005% in patients who have uncontrolled intraocular pressure (IOP) using timolol 0.5% and dorzolamide 2%. METHODS: Fifty-two consecutive patients with open-angle glaucoma who were using timolol and dorzolamide and were considered to have IOP above their defined target pressure were included in this study. After a baseline diurnal tension curve (DTC) was performed, latanoprost once a day was added to the treatment, and a second DTC was performed 1 week later. RESULTS: Five patients (9.6%) were discontinued from treatment because of side effects. The remaining 47 patients showed a significant IOP reduction of 3.1 mm Hg (16%) from a baseline of 19.3 mm Hg (mean IOP registered during DTC; P < or = 0.0001). Seventeen patients (36.3%) showed a mean IOP reduction greater than 20%. CONCLUSIONS: Latanoprost had an additive effect when used as a third drug for patients on timolol and dorzolamide who were in need of further IOP reduction. These results suggest that latanoprost may be very effective in some patients with poorly controlled glaucoma on multiple therapy.     

Efficacy and safety of the latanoprost/timolol maleate fixed combination vs concomitant brimonidine and latanoprost therapy

AIMS: To evaluate the efficacy and safety of latanoprost/timolol maleate fixed combination (LTFC) given once daily vs the concomitant therapy of brimonidine twice daily and latanoprost once daily in primary open-angle glaucoma or ocular hypertensive subjects. METHODS: A prospective, double-masked, active-controlled comparison in which qualified subjects had all glaucoma medicines discontinued for 1 month and then were randomized to either LTFC or brimonidine and latanoprost concomitant therapy for 6 weeks. They were then switched to the other treatment regimen. The intraocular pressure (IOP) was measured at 0800, 1200, and 1600 h at baseline and at the end of Periods 1 and Period 2. RESULTS: In 32 subjects, the diurnal curve of the untreated IOP of 26.0+/-3.4 decreased to 17.8+/-2.5 on LTFC and 17.2+/-2.8 mmHg on brimonidine and latanoprost (P=0.31). At 0800 and 1600 h, the IOPs were statistically similar between the groups (P>0.05). At 1200 h the latanoprost and brimonidine treatment IOP was statistically lower (16.2+/-3.2) than LTFC (18.0+/-2.8 mmHg). However, the reduced IOP from untreated baseline was not statistically different at each time point and for the diurnal curve for each therapy (P<0.05). Safety was similar between groups for both solicited and unsolicited side effects (P>0.05). CONCLUSION: This study suggests that LTFC and concomitant therapy of brimonidine and latanoprost provide statistically similar diurnal IOP reduction from an untreated baseline.     

Conjunctival proinflammatory and proapoptotic effects of latanoprost and preserved and unpreserved timolol: an ex vivo and in vitro study

PURPOSE: To compare the toxicity of latanoprost and preserved and unpreserved timolol on conjunctival cells. Expression of inflammatory markers and MUC5AC-related mucin production were evaluated by impression cytology in a case-control ex vivo study. The proapoptotic effect of the same drugs was also evaluated in vitro in a conjunctival cell line and compared with that of benzalkonium chloride (BAC). METHODS: Impression cytology (IC) specimens were obtained from a series of normal subjects and from patients with glaucoma treated for at least 1 year with latanoprost eye drops or preserved or unpreserved timolol. All groups were comparable in age and duration of treatment. Expression of HLA-DR, intercellular adhesion molecule (ICAM)-1, and mucin was evaluated in a masked manner by flow cytometry. For the in vitro study, a human conjunctiva-derived cell line was treated with 0.02% BAC-containing latanoprost or timolol, unpreserved timolol, or 0.02% BAC alone for 15 minutes, followed or not by 4 or 24 hours of cell recovery in normal medium. Cell viability and chromatin condensation were evaluated using microplate cold light cytofluorometry with the neutral red and the Hoechst 33342 tests, respectively. The Hoechst-neutral red ratio was defined for the apoptosis assay, and cytoskeleton changes were assessed by confocal microscopy. RESULTS: No difference was found between normal eyes and those receiving unpreserved timolol. Preserved latanoprost and timolol significantly increased the inflammatory marker expression and decreased MUC5AC expression, but to a significantly higher extent in the preserved timolol group compared with latanoprost. In vitro, 0.02% BAC-containing timolol and latanoprost triggered conjunctival cell apoptosis-however, to a significantly lesser extent than did 0.02% BAC alone. Unpreserved timolol did not cause any cell toxicity. CONCLUSIONS: These ex vivo and in vitro studies demonstrate that BAC-containing latanoprost and timolol exhibit higher proinflammatory and proapoptotic effects on conjunctival cells than does unpreserved timolol. Latanoprost caused less toxicity, however, than preserved timolol, and both drugs were less toxic than BAC alone. These results suggest a potential protective effect of the prostaglandin analogue and to a lesser extent of timolol against the toxicity of BAC in conjunctival cells.     

Effect of latanoprost and timolol on the histopathology of the rabbit conjunctiva

PURPOSE. Long-term medical treatment of glaucoma has an effect on the conjunctiva, possibly affecting the outcome of subsequent filtering surgery. The type and extent of these tissue changes caused by frequently used medications is important. An animal study using rabbits was performed to assess the tissue changes caused by timolol, latanoprost, and a combination of both substances. METHODS. Rabbits were treated with timolol, latanoprost, or a combination of these drugs for 18 months. Conjunctival specimens were examined by light microscopy, quantitative transmission electron microscopy, and immunohistochemistry with antibodies against matrix metalloproteinase (MMP)-3 and tissue inhibitors of metalloproteinase (TIMP)-2. RESULTS. By electron microscopy, the area of subepithelial collagen was significantly larger (P: < 0.03; Mann-Whitney test) in timolol-treated eyes (71.6%) than in control (52.7%) and latanoprost-treated eyes (57.7%). An increase of amorphous material was present in timolol-treated eyes (25.6% versus 7.6% in the controls) as well as a smaller area of empty spaces (2.5% versus 39.4% in control eyes). Latanoprost-treated eyes had no significant increase of empty spaces but showed a marked staining for MMP-3 in the conjunctiva. This staining was not present in control or timolol-treated eyes. Morphologically, degenerative changes of fibrocytes were seen in timolol-treated eyes only. CONCLUSIONS. A significant increase of subepithelial collagen density was present in timolol-treated eyes, whereas this finding was not apparent in latanoprost-treated eyes. Latanoprost-treated eyes showed an upregulation of MMP-3, which may be the reason for reduced extracellular matrix accumulation in such eyes. The morphologic feature of increased subepithelial collagen density and extracellular matrix changes may relate to failure of filtering blebs.     

Efficacy and safety of timolol maleate/latanoprost fixed combination versus timolol maleate and brimonidine given twice daily

PURPOSE: To evaluate the efficacy and safety of the timolol maleate/latanoprost fixed combination (TLFC) given once each evening versus brimonidine and timolol solution given twice daily as concomitant therapy in primary open-angle glaucoma or ocular hypertension patients. METHODS: Qualified subjects were begun on timolol alone twice daily for 1 month and then randomized to either TLFC or brimonidine and timolol concomitant therapy for 6 weeks. Patients were then switched to the other treatment regimen. Intraocular pressures (IOPs) were measured every 2 hours between 08 : 00 and 20 : 00 hours at baseline and at the end of periods 1 and 2. RESULTS: This study found that in 32 subjects the IOP diurnal curve on timolol alone (20.9 +/- 2.8 mmHg) decreased to 17.9 +/- 3.2 mmHg when patients were treated with TLFC and to 19.0 +/- 2.4 mmHg when patients were treated with brimonidine and timolol (p = 0.02). Intraocular pressures at individual time-points were statistically similar between the groups at the 08 : 00 trough and 2 and 4 hours after dosing. However, beyond 4 hours after dosing, TLFC-treated subjects demonstrated a trend towards lower IOPs at each 2-hour time-point that was not statistically significant after a Bonferroni correction (p 相似文献   

Comparison of two fixed combinations of latanoprost and timolol in open-angle glaucoma

· Objective: To compare the intraocular pressure (IOP)-reducing effect of the fixed combinations of timolol 0.5% and latanoprost 0.001% or 0.005% after 4 weeks’ treatment. · Design: Following a 1-week run-in period on timolol 0.5% once daily, 139 patiens were randomized to once-daily treatment with a fixed combination of timolol 0.5% and latanoprost 0.001% (comb. 10) or latanoprost 0.005% (comp. 50) or to the individual monotherapies. The IOP was measured at inclusion and at 8 a.m., noon and 4 p.m. on days 1, 7 and 28. · Results: Comb. 10, comb. 50, latanoprost and timolol reduced IOP by 3.7, 6.1, 4.9 and 2.1 mmHg, respectively, from a baseline mean diurnal IOP (±SEM) of 24.8±0.5, 24.1±0.4, 25.2±1.2 and 24.8±0.9 mmHg, respectively. The difference in IOP reduction was significant between comb. 50 and comb. 10 (P<0.001), latanoprost (P=0.046) and timolol (P<0.001) in favor of comb. 50. There was also a significant difference between latanoprost and timolol (P=0.007), in favor of latanoprost. All treatments were generally well tolerated. · Conclusion: This study indicates that a fixed combination of latanoprost 0.005% and timolol 0.5% could be useful in the treatment of glaucoma. Received: 6 October 1997 Revised version received: 16 December 1997 Accepted: 7 January 1998     

A 12-month, randomized, double-masked study comparing latanoprost with timolol in pigmentary glaucoma

OBJECTIVE: To compare the efficacy and side effects and the effect on aqueous humor dynamics of 0.005% latanoprost applied topically once daily with 0.5% timolol given twice daily for 12 months to patients with pigmentary glaucoma. DESIGN: Prospective, randomized, double-masked, clinical study. PARTICIPANTS: Thirty-six patients affected with bilateral pigmentary glaucoma controlled with no more than a single hypotensive medication were enrolled in the study. INTERVENTION: The sample population was randomly divided into 2 age- and gender-matched groups each of 18 patients. Group 1 received 0.005% latanoprost eyedrops once daily and the vehicle (placebo) once daily; group 2 was assigned to timolol 0.5% eyedrops twice daily. MAIN OUTCOME MEASURES: Diurnal curves of intraocular pressure (IOP) were performed on the baseline day and after 0.5, 3, 6, and 12 months of treatment. The IOP measurements were performed at 8:00 AM, 12:00 noon, 4:00 PM, and 8:00 PM. Outflow facility ("C") was measured on the baseline day and on the last day of the study with a Schiotz electronic tonometer. A two-tailed Student's t test for paired or unpaired data was used for statistical evaluation of differences between treatment and baseline values or between the latanoprost and timolol group. Diurnal IOP measurements were compared hour by hour. Mean values of the two eyes IOP and "C" were used for analysis. RESULTS: Compared with baseline measurements, both latanoprost and timolol caused a significant (P < 0.001) reduction of IOP at each hour of diurnal curve throughout the duration of therapy. Reduction of IOP was 6.0 +/- 4.5 and 5.9 +/- 4.6 with latanoprost and 4.8 +/- 3.0 and 4.6 +/- 3.1 with timolol after 6 and 12 months, respectively. Comparison of mean diurnal measurements with latanoprost and timolol showed a statistical significant (P < 0.001) difference at 3, 6, and 12 months. Mean "C" was found to be significantly enhanced (+30%) only in the latanoprost-treated group compared with the baseline (P = 0.017). Mean conjunctival hyperemia was graded at 0.3 in latanoprost-treated eyes and 0.2 in timolol-treated eyes. A remarkable change in iris color was observed in both eyes of 1 of the 18 patients treated with latanoprost and none of the 18 patients who received timolol. Darkening of the peripheral iris stroma was suspected in two patients treated with latanoprost. In the timolol group, heart rate was significantly reduced from 72 +/- 9 at baseline to 67 +/- 10 beats per minute at 12 months. CONCLUSIONS: Although further studies may need to confirm these data on a larger sample and to evaluate the side effect of increased iris pigmentation on long-term follow-up, in patients with pigmentary glaucoma, 0.005% latanoprost taken once daily was well tolerated and more effective in reducing IOP than 0.5% timolol taken twice daily.     

Additive IOP-reducing effect of latanoprost in patients insufficiently controlled on timolol

PURPOSE: To evaluate the effect on intraocular pressure (IOP) of switching from timolol to latanoprost or adding latanoprost to timolol in patients with open angle glaucoma or ocular hypertension where IOP is not adequately controlled with timolol. METHODS: This was a 6-week, double-masked, randomised multi-centre study. 53 patients with primary open angle glaucoma, capsular glaucoma, or ocular hypertension with an IOP of at least 21 mmHg on current therapy were recruited. After a run-in period of at least 2 weeks on timolol, 5 mg/ml twice daily, patients were randomised to one of three groups. One group continued on timolol, one switched from timolol to latanoprost, 50 microg/ml once daily, and a third group received latanoprost in addition to timolol. The efficacy was evaluated by comparing IOP at 9 AM at baseline and after 6 weeks of treatment. RESULTS: IOP at baseline and after 6 weeks of treatment (mean +/- SEM) were 24.2 +/- 0.9 and 23.8 +/- 1.0 mmHg (n = 16) for patients continuing on timolol, 26.3 +/- 1.2 and 19.6 +/- 1.1 mmHg (n = 17) for patients switching to latanoprost, and 23.2 +/- 1.0 and 17.5 +/- 0.8 mmHg (n = 17) for patients with combined treatment. Adding latanoprost to timolol reduced IOP with 5.9 +/- 0.9 mmHg (p < 0.001) and switching from timolol to latanoprost reduced IOP with 5.0 +/- 0.9 mmHg (p < 0.001), which caused in each group a significant IOP reduction of about 25%. CONCLUSIONS: The effect of latanoprost was additive to that of timolol, and a good effect on IOP reduction was also achieved by switching from timolol to latanoprost, suggesting that a switch in many patients is an effective alternative to combination treatment.