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William C. Stewart - One of the best experts on this subject based on the ideXlab platform.

  • A Comfort Survey of Timolol Hemihydrate 0.5% Solution Once or Twice Daily vs Timolol Maleate in Sorbate.
    Journal of current glaucoma practice, 2013
    Co-Authors: William C. Stewart, Jeffrey C Oehler, Neil T Choplin, Joseph I Markoff, Marlene R. Moster, Parul Ichhpujani, Lindsay A. Nelson
    Abstract:

    Objective To evaluate by survey the comfort upon instillation of Timolol hemihydrate compared to Timolol maleate with potassium sorbate. Design A prospective, multicenter, observational, non-interventional study. Participants One hundred and three patients of open-angle glaucoma or ocular hypertension who were ≥21 years old and were currently prescribed Timolol hemihydrate (once or twice daily) or Timolol maleate with potassium sorbate once daily as monotherapy or as a part of two-drug therapy. Materials and methods Study was performed at seven clinical sites in the United States. Patients were surveyed on comfort upon instillation of Timolol hemihydrate compared to Timolol maleate with potassium sorbate. Results A difference between Timolol hemihydrate and Timolol maleate with potassium sorbate for questions 1 (burning/stinging on instillation, p 0.05). Conclusion This survey suggests that Timolol hemihydrate is associated with less stinging/burning and tearing than Timolol maleate with potassium sorbate. How to cite this article: Stewart WC, Oehler JC, Choplin NT, Markoff JI, Moster MR, Ichhpujani P, Nelson LA. A Comfort Survey of Timolol Hemihydrate 0.5% Solution Once or Twice Daily vs Timolol Maleate in Sorbate. J Current Glau Prac 2013;7(1):11-16.

  • 24-Hour Control With a Latanoprost-Timolol Fixed Combination vs Timolol Alone
    Archives of ophthalmology (Chicago Ill. : 1960), 2006
    Co-Authors: Anastasios G. P. Konstas, Symeon Lake, Athanasios I. Economou, Kostantinos Kaltsos, Jessica N. Jenkins, William C. Stewart
    Abstract:

    Objective To evaluate 24-hour intraocular pressure (IOP) control with an evening-dosed latanoprost–Timolol maleate fixed combination vs Timolol alone in patients with primary open-angle glaucoma. Methods After a medicine-free period, qualified patients were randomized to either placebo dosed in the morning with a latanoprost-Timolol fixed combination dosed in the evening or Timolol alone dosed twice daily for 8 weeks. Patients were then switched to the opposite treatment for 8 weeks. At baseline and at the end of each treatment period, patients underwent IOP measurements. Results Both treatments reduced the IOP from untreated baseline at each time point and for the 24-hour curve ( P P P  = .003) and for the 24-hour curve. Several adverse effects were observed more often with the latanoprost-Timolol fixed combination, including ocular stinging ( P  = .05), conjunctival hyperemia ( P  = .02), and ocular itching ( P  = .04). Conclusion The evening-dosed latanoprost-Timolol fixed combination may provide better IOP control than Timolol alone over 24 hours and may demonstrate a narrower range of IOP fluctuation in patients with primary open-angle glaucoma.

  • Differences in ocular surface irritation between Timolol hemihydrate and Timolol maleate
    American journal of ophthalmology, 2000
    Co-Authors: William C. Stewart, Jeanette A. Stewart, Keri T Holmes, Jessica N. Leech
    Abstract:

    Abstract PURPOSE: We evaluated the anterior segment surface reaction findings between Timolol hemihydrate and Timolol maleate. The only known difference between these preparations is the maleate salt. METHODS: After a baseline examination, we randomized 28 healthy subjects (26 completed) to Timolol hemihydrate or Timolol maleate given in both eyes twice daily, in a double masked fashion, for 1 week. Subjects then were evaluated at the morning trough (hour 0 examination), dosed, and re-evaluated in 1 hour (hour 1 examination). Subjects were left untreated for 1 week and then switched to the opposite medication for the second study period. RESULTS: Corneal staining (graded 0 to 4) for Timolol maleate was worse between baseline (0.9) and hour 0 (1.4; P = .009) and baseline and hour 1 (1.4; P = .011). Also, mean punctate corneal staining for Timolol maleate was increased from baseline (22.6) to hour 0 (31.7; P = .033) and showed borderline significance to hour 1 (33.4; P = .058), and for Timolol hemihydrate there was a borderline significant elevation from baseline (24.2) to hour 1 (29.8; P = .060). When treatment groups were compared, there was a greater change in corneal staining with Timolol maleate than Timolol hemihydrate from baseline to hour 0 (P = .020) and greater staining with Timolol maleate than Timolol hemihydrate at hour 0 (P = .032). Nasal conjunctiva showed increased mean staining with Timolol maleate from baseline (23.6, P = .035) to hour 0 (29.5, P = .035) and to hour 1 (31.9 P = .038) but not with Timolol hemihydrate. There were increased symptoms of ocular dryness from baseline to hour 0 with Timolol maleate (P = .012) but not with Timolol hemihydrate. CONCLUSIONS: The study suggests that Timolol maleate potentially may have more of an irritant effect than Timolol hemihydrate on the corneal and nasal conjunctival epithelium.

  • Efficacy and safety of Timolol solution once daily vs Timolol gel added to latanoprost
    American journal of ophthalmology, 1999
    Co-Authors: William C. Stewart, Harvey Dubiner, Keri T Holmes, Douglas G. Day, Elizabeth D. Sharpe, Jeanette A. Stewart
    Abstract:

    Abstract 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 β-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.

  • The safety and efficacy of switching Timolol maleate 0.5% solution to Timolol hemihydrate 0.5% solution given twice daily.
    Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics, 1998
    Co-Authors: Thomas K. Mundorf, Jeanette A. Stewart, Elin A. Cate, Cheryl S. Sine, Donna W. Otero, William C. Stewart
    Abstract:

    This study was undertaken to evaluate the safety and efficacy of switching patients treated with Timolol maleate to Timolol hemihydrate. In patients with ocular hypertension or chronic open-angle glaucoma treated with beta-blockers for at least three months, we prescribed Timolol maleate solution 0.5% given twice daily for one month. We then switched each patient to Timolol hemihydrate solution 0.5% (Betimol, Ciba Vision Ophthalmics) given twice daily for three months. This study found over the first three months in 30 completed subjects, using a worse eye analysis, that the intraocular pressure changed from 18.3+/-2.1 mm Hg on Timolol maleate to 18.8+/-2.3 mm Hg on Timolol hemihydrate (P=0.10) 12 hours after dosing. There was no difference in the overall incidence of unsolicited anterior segment side effects between Timolol maleate (4 cases) versus Timolol hemihydrate (3 cases) (P=0.69). One patient exited the study because of pain and burning in both eyes while on Timolol maleate. No patient was discontinued due to loss of intraocular pressure control after switching to Timolol hemihydrate. It was concluded that switching from Timolol maleate to Timolol hemihydrate is safe and effective in maintaining control of the intraocular pressure.

Jeanette A. Stewart - One of the best experts on this subject based on the ideXlab platform.

  • Differences in ocular surface irritation between Timolol hemihydrate and Timolol maleate
    American journal of ophthalmology, 2000
    Co-Authors: William C. Stewart, Jeanette A. Stewart, Keri T Holmes, Jessica N. Leech
    Abstract:

    Abstract PURPOSE: We evaluated the anterior segment surface reaction findings between Timolol hemihydrate and Timolol maleate. The only known difference between these preparations is the maleate salt. METHODS: After a baseline examination, we randomized 28 healthy subjects (26 completed) to Timolol hemihydrate or Timolol maleate given in both eyes twice daily, in a double masked fashion, for 1 week. Subjects then were evaluated at the morning trough (hour 0 examination), dosed, and re-evaluated in 1 hour (hour 1 examination). Subjects were left untreated for 1 week and then switched to the opposite medication for the second study period. RESULTS: Corneal staining (graded 0 to 4) for Timolol maleate was worse between baseline (0.9) and hour 0 (1.4; P = .009) and baseline and hour 1 (1.4; P = .011). Also, mean punctate corneal staining for Timolol maleate was increased from baseline (22.6) to hour 0 (31.7; P = .033) and showed borderline significance to hour 1 (33.4; P = .058), and for Timolol hemihydrate there was a borderline significant elevation from baseline (24.2) to hour 1 (29.8; P = .060). When treatment groups were compared, there was a greater change in corneal staining with Timolol maleate than Timolol hemihydrate from baseline to hour 0 (P = .020) and greater staining with Timolol maleate than Timolol hemihydrate at hour 0 (P = .032). Nasal conjunctiva showed increased mean staining with Timolol maleate from baseline (23.6, P = .035) to hour 0 (29.5, P = .035) and to hour 1 (31.9 P = .038) but not with Timolol hemihydrate. There were increased symptoms of ocular dryness from baseline to hour 0 with Timolol maleate (P = .012) but not with Timolol hemihydrate. CONCLUSIONS: The study suggests that Timolol maleate potentially may have more of an irritant effect than Timolol hemihydrate on the corneal and nasal conjunctival epithelium.

  • Efficacy and safety of Timolol solution once daily vs Timolol gel added to latanoprost
    American journal of ophthalmology, 1999
    Co-Authors: William C. Stewart, Harvey Dubiner, Keri T Holmes, Douglas G. Day, Elizabeth D. Sharpe, Jeanette A. Stewart
    Abstract:

    Abstract 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 β-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.

  • The safety and efficacy of switching Timolol maleate 0.5% solution to Timolol hemihydrate 0.5% solution given twice daily.
    Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics, 1998
    Co-Authors: Thomas K. Mundorf, Jeanette A. Stewart, Elin A. Cate, Cheryl S. Sine, Donna W. Otero, William C. Stewart
    Abstract:

    This study was undertaken to evaluate the safety and efficacy of switching patients treated with Timolol maleate to Timolol hemihydrate. In patients with ocular hypertension or chronic open-angle glaucoma treated with beta-blockers for at least three months, we prescribed Timolol maleate solution 0.5% given twice daily for one month. We then switched each patient to Timolol hemihydrate solution 0.5% (Betimol, Ciba Vision Ophthalmics) given twice daily for three months. This study found over the first three months in 30 completed subjects, using a worse eye analysis, that the intraocular pressure changed from 18.3+/-2.1 mm Hg on Timolol maleate to 18.8+/-2.3 mm Hg on Timolol hemihydrate (P=0.10) 12 hours after dosing. There was no difference in the overall incidence of unsolicited anterior segment side effects between Timolol maleate (4 cases) versus Timolol hemihydrate (3 cases) (P=0.69). One patient exited the study because of pain and burning in both eyes while on Timolol maleate. No patient was discontinued due to loss of intraocular pressure control after switching to Timolol hemihydrate. It was concluded that switching from Timolol maleate to Timolol hemihydrate is safe and effective in maintaining control of the intraocular pressure.

  • Efficacy and safety of Timolol solution once daily versus Timolol gel in treating elevated intraocular pressure.
    Journal of glaucoma, 1998
    Co-Authors: William C. Stewart, T M Leland, E A Cate, Jeanette A. Stewart
    Abstract:

    Purpose To evaluate the efficacy and safety of Timolol hemihydrate once daily versus Timolol maleate gel forming solution once daily in patients with primary open-angle glaucoma or ocular hypertension. Methods We prospectively randomized patients with primary open-angle glaucoma or ocular hypertension to receive either Timolol hemihydrate 0.5% solution or Timolol maleate gel forming solution 0.5% every morning. The primary efficacy variable was the 8:00 AM trough intraocular pressure (IOP) 24 hours after administration. Results Three months after initiation of therapy, baseline IOP had decreased from 23.6 +/- 1.9 mmHg to 18.3 +/- 2.8 mmHg in the group taking Timolol hemihydrate (n = 22) and from 23.7 +/- 2.2 mmHg to 18.4 +/- 3.1 mmHg in the group receiving Timolol maleate gel (n = 21) at the 24-hour trough level. This was not a significant difference between groups at 3 months. Also, no difference was observed between groups in the 2-hour post instillation IOP. Visual acuity was decreased in the group receiving Timolol maleate gel compared with those receiving Timolol hemihydrate one minute after instillation of study medicine at month 3. Otherwise, ocular and systemic safety were similar between groups. No differences between groups in cardiac pulse or systolic and diastolic blood pressure were observed. Conclusion Timolol hemihydrate 0.5% solution given once a day appears to be as efficacious and safe in decreasing IOP as Timolol maleate gel 0.5% given once a day.

Harvey Dubiner - One of the best experts on this subject based on the ideXlab platform.

  • twice daily 0 2 brimonidine 0 5 Timolol fixed combination therapy vs monotherapy with Timolol or brimonidine in patients with glaucoma or ocular hypertension a 12 month randomized trial
    Archives of Ophthalmology, 2006
    Co-Authors: Mark B Sherwood, Harvey Dubiner, Rhett M Schiffman, Randy E Craven, Connie Chou, Amy L Batoosingh, Scott M Whitcup
    Abstract:

    Objective To evaluate the intraocular pressure (IOP)–lowering efficacy and safety of a fixed combination of 0.2% brimonidine tartrate and 0.5% Timolol maleate (fixed brimonidine-Timolol) compared with the component medications. Methods In 2 identical, 12-month, randomized, double-masked multicenter trials, patients with ocular hypertension or glaucoma were treated with fixed brimonidine-Timolol twice daily (n = 385), 0.2% brimonidine tartrate 3 times daily (n = 382), or 0.5% Timolol maleate twice daily (n = 392). Main Outcomes Measures Mean change from baseline IOP and incidence of adverse events. Results The mean decrease from baseline IOP during 12-month follow-up was 4.4 to 7.6 mm Hg with fixed brimonidine-Timolol, 2.7 to 5.5 mm Hg with brimonidine, and 3.9 to 6.2 mm Hg with Timolol. Mean IOP reductions were significantly greater with fixed brimonidine-Timolol compared with Timolol at all measurements (P≤.002) and brimonidine at 8AM, 10AM, and 3PM(P Conclusions Twice-daily fixed brimonidine-Timolol therapy provides sustained IOP lowering superior to monotherapy with either thrice-daily brimonidine or twice-daily Timolol and is better tolerated than brimonidine but less well tolerated than Timolol. Application to Clinical Practice Fixed brimonidine-Timolol is an effective and convenient IOP-lowering therapy.

  • Efficacy and safety of Timolol solution once daily vs Timolol gel added to latanoprost
    American journal of ophthalmology, 1999
    Co-Authors: William C. Stewart, Harvey Dubiner, Keri T Holmes, Douglas G. Day, Elizabeth D. Sharpe, Jeanette A. Stewart
    Abstract:

    Abstract 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 β-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.

  • The efficacy and safety of the dorzolamide-Timolol combination versus the concomitant administration of its components.
    Ophthalmology, 1998
    Co-Authors: Kim M. Strohmaier, Ellen Snyder, Harvey Dubiner, Ingrid Adamsons
    Abstract:

    Abstract Objective To evaluate whether a fixed combination of 2% dorzolamide and 0.5% Timolol given twice daily showed equivalent efficacy to the concomitant administration of 2% dorzolamide given three times daily and 0.5% Timolol given twice daily in patients whose intraocular pressure (IOP) remained elevated during monotherapy with 0.5% Timolol twice daily. Design Multicenter, parallel, randomized, double-masked clinical trial with an open-label extension. Participants and intervention In the masked phase, 242 patients received either the dorzolamide-Timolol combination twice daily and placebo three times daily or dorzolamide three times daily and Timolol twice daily for up to 3 months. In the open-label extension, 220 patients received the dorzolamide-Timolol combination twice daily for up to 9 months. Main outcome measures The criterion for establishing treatment equivalency was a 95% or greater confidence that the absolute difference in the mean change in IOP from baseline was less than 1.5 mmHg between treatments. Results During 3 months of treatment, the dorzolamide-Timolol combination reduced IOP relative to the 0.5% Timolol baseline by approximately 14% at hour 0 (just before the morning dose), 20% at hour 2, and 15% at hour 8. The IOP-lowering effect of concomitant therapy with dorzolamide and Timolol was approximately 16% at hour 0, 20% at hour 2, and 17% at hour 8. At hours 0, 2, and 8, there was greater than 97% confidence that the treatments were equivalent. During the open-label extension, the mean IOP reduction ranged from 14% to 15% at hour 0 and from 20% to 21% at hour 2. The treatment groups were generally comparable in terms of adverse events, symptoms, ocular signs, visual acuity, visual fields, physical examination, and laboratory measures. Conclusions The IOP-lowering effect of the dorzolamide-Timolol combination is comparable to that of dorzolamide three times daily plus Timolol twice daily and is maintained for up to 1 year. The dorzolamide-Timolol combination provides clinically important reduction in IOP relative to baseline treatment with Timolol alone and is generally well-tolerated for up to 1 year.

  • Timolol Hemihydrate vs Timolol Maleate to Treat Ocular Hypertension and Open-Angle Glaucoma
    American journal of ophthalmology, 1996
    Co-Authors: Harvey Dubiner, Richard A. Hill, Herbert E. Kaufman, Edwin U. Keates, Thom J. Zimmerman, Alan I. Mandell, Thomas K. Mundorf, Robert L. Bahr, Louis W. Schwartz, Anne W. Towey
    Abstract:

    • Purpose: We compared the therapeutic efficacy and safety of Timolol hemihydrate to Timolol maleate in patients with ocular hypertension and chronic open-angle glaucoma. • Methods: We conducted this three-month study as a multicentered, masked, parallel group comparison. Both the 0.25% and 0.5% concentrations were evaluated against similar concentrations of Timolol maleate. Dosing was twice daily. An open-label, nine-month study followed the masked portion of the protocol, in which all patients received either 0.25% or 0.5% Timolol hemihydrate. A total of 371 patients were included in both the 0.25% and 0.5% studies. • Results: We found statistically similar intraocular pressures with both the 0.25% (18.3 and 18.6 mm Hg for the hemihydrate and maleate groups, respectively) and 0.5% (19.9 and 19.5 mm Hg for the hemihydrate and maleate groups, respectively) concentrations of Timolol hemihydrate and Timolol maleate after three months of masked treatment. Likewise, peak intraocular effect at two hours after taking the medication was statistically similar between medicines at both concentrations. Likewise, both ocular and systemic safety were similar between the maleate and hemihydrate preparations at both concentrations. In the nine-month open-label protocol, therapeutic efficacy (19.9 and 19.1 mm Hg for the 0.25% and 0.5% concentrations, respectively) and safety of Timolol hemihydrate were similar to effect and safety of the three-month protocol. • Conclusions: This study suggests that Timolol hemihydrate had an ocular hypotensive efficacy and safety profile statistically equivalent to that of Timolol maleate for up to three months of therapy. Timolol hemihydrate showed efficacy and safety similar to that observed within the first three months, for up to one year of therapy.

Christophe Baudouin - One of the best experts on this subject based on the ideXlab platform.

  • Polyquad-preserved travoprost/Timolol, benzalkonium chloride (BAK)-preserved travoprost/Timolol, and latanoprost/Timolol in fixed combinations: a rabbit ocular surface study
    Advances in Therapy, 2011
    Co-Authors: Hong Liang, Françoise Brignole-baudouin, Luisa Riancho, Aude Pauly, Christophe Baudouin
    Abstract:

    Introduction The aim of this study was to use a validated acute rabbit model to test the toxicity of a novel formulation of fixed-combination travoprost 0.004%/Timolol 0.5% ophthalmic solution, which contains the antimicrobial preservative polyquaternium-1 (PQ), compared with the commercial formulation of fixed combinations travoprost 0.004%/Timolol 0.5% ophthalmic solution and latanoprost 0.005%/Timolol 0.5% ophthalmic solution, which both contain the preservative benzalkonium chloride (BAK). Methods Adult male New Zealand albino rabbits ( n =24) were randomly divided into four groups. Phosphatebuffered saline (PBS), travoprost/Timolol PQ, travoprost/Timolol BAK, or latanoprost/Timolol BAK were instilled onto rabbit eyes one drop, 15 times at 5 minute intervals. The ocular surface reactions were investigated at hour 4 and day 1 using slit lamp examination; in-vivo confocal microscopy (IVCM) for cornea, limbus, and conjunctiva-associated lymphoid tissue (CALT); conjunctival impression cytology; and standard immunohistology in cryosections for detecting CD45+ infiltrating cells and MUC-5AC-labeled cells. Results Travoprost/Timolol PQ was better tolerated than travoprost/Timolol BAK or latanoprost/Timolol BAK. This improved tolerance was evident via clinical observation under slit lamp, IVCM in different layers of the cornea and conjunctiva, conjunctival impression cytology of superficial epithelium aspects, and immunohistochemistry for inflammatory infiltration of CD45+ cells in the cornea and goblet cell distribution. Travoprost/Timolol PQ was similar to PBS in regards to in-vivo findings, the Draize test for ocular irritation, and epithelial and limbal aspects as evaluated with IVCM. Treatment with either travoprost/Timolol PQ or PBS produced no obvious inflammatory infiltration inside and outside the CALT follicles, yielded similar IVCM toxicity scores and CD45+ cell counts, and eyes treated with either solution had normal goblet cells. Conclusion The fixed combination of travoprost/Timolol with 0.001% PQ had decreased ocular surface toxicity relative to the BAK-containing solutions. The potential benefit to the human ocular surface with oncedaily dosing needs to be evaluated clinically.

  • In vitro comparative toxicology of polyquad-preserved and benzalkonium chloride-preserved travoprost/Timolol fixed combination and latanoprost/Timolol fixed combination.
    Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics, 2011
    Co-Authors: Françoise Brignole-baudouin, Hong Liang, Luisa Riancho, Zaki Nakib, Christophe Baudouin
    Abstract:

    Abstract Purpose: To compare, in vitro, the cytotoxicity profile of a new formulation of travoprost 0.004%/Timolol 0.5% fixed combination ophthalmic solution preserved with polyquaternium-1 0.001% (travoprost/Timolol PQ) instead of benzalkonium chloride (BAK) with (1) commercially available travoprost 0.004%/Timolol 0.5% fixed combination ophthalmic solution (travoprost/Timolol BAK), (2) commercially available latanoprost 0.005%/Timolol 0.5% fixed combination ophthalmic solution (latanoprost/Timolol BAK), and (3) their associated BAK concentrations. Methods: Compounds tested on Wong–Kilbourne-derived human conjunctival epithelial cells: (1) phosphate-buffered saline, (2) polyquaternium-1 0.001% (Polyquad®, PQ), (3) travoprost/Timolol PQ, (4) travoprost/Timolol BAK with 0.015% BAK (DuoTrav®), (5) BAK 0.015%, (6) latanoprost/Timolol BAK with 0.020% BAK (Xalacom®), and (7) BAK 0.020%. Toxicological assays were used to assess cell viability [neutral red (NR), Alamar blue (AB)], apoptosis (YO-PRO-1, Hoechst 33...

  • conjunctival proinflammatory and proapoptotic effects of latanoprost and preserved and unpreserved Timolol an ex vivo and in vitro study
    Investigative Ophthalmology & Visual Science, 2004
    Co-Authors: Pierrejean Pisella, C Debbasch, P Hamard, C Creuzotgarcher, Patrice Rat, F Brignole, Christophe Baudouin
    Abstract:

    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.

Auli Ropo - One of the best experts on this subject based on the ideXlab platform.

  • Ophthalmic Timolol in a hydrogel vehicle leads to minor inter-individual variation in Timolol concentration in aqueous humor.
    European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, 2008
    Co-Authors: Marjo Volotinen, Auli Ropo, Jukka Mäenpää, Heikki Vapaatalo, H Kautiainen, A Tolonen, J Uusitalo, Esko Aine
    Abstract:

    Ophthalmic Timolol has been used for decades in the treatment of glaucoma and ocular hypertension, traditionally in aqueous 0.5% eye drops. Recently a Timolol 0.1% hydrogel has been developed to improve systemic safety. The aim of the present study was to compare aqueous humor Timolol concentrations after administration of 0.1% hydrogel and aqueous 0.5% Timolol in patients scheduled for a cataract operation. The concentration in the aqueous humor was 210+/-175 ng/ml (mean+/-S.D.) 2h after administration of Timolol 0.1% hydrogel and 538+/-304 ng/ml after aqueous 0.5% Timolol. In the aqueous 0.5% Timolol group more patients had unnecessarily high concentrations of Timolol in the aqueous humor. beta(1)-receptors and beta(2)-receptors were practically 100% occupied after administration of both products. The hydrogel proved to be an excellent formulation in giving smaller inter-individual variation in penetration of Timolol into the aqueous humor. Only a weak correlation was seen between corneal thickness and the aqueous humor concentration of Timolol in the aqeuous 0.5% Timolol group. In conclusion, in contrast to the conventional aqueous 0.5% Timolol, 0.1% Timolol hydrogel caused only slight inter-individual variation in Timolol concentration in the aqueous humor.

  • Ophthalmic Timolol in a hydrogel vehicle leads to minor inter-individual variation in Timolol concentration in aqueous humor.
    European Journal of Pharmaceutical Sciences, 2008
    Co-Authors: Marjo Volotinen, Auli Ropo, Jukka Mäenpää, Heikki Vapaatalo, H Kautiainen, A Tolonen, J Uusitalo, Esko Aine
    Abstract:

    Abstract Ophthalmic Timolol has been used for decades in the treatment of glaucoma and ocular hypertension, traditionally in aqueous 0.5% eye drops. Recently a Timolol 0.1% hydrogel has been developed to improve systemic safety. The aim of the present study was to compare aqueous humor Timolol concentrations after administration of 0.1% hydrogel and aqueous 0.5% Timolol in patients scheduled for a cataract operation. The concentration in the aqueous humor was 210 ± 175 ng/ml (mean ± S.D.) 2 h after administration of Timolol 0.1% hydrogel and 538 ± 304 ng/ml after aqueous 0.5% Timolol. In the aqueous 0.5% Timolol group more patients had unnecessarily high concentrations of Timolol in the aqueous humor. β 1 -receptors and β 2 -receptors were practically 100% occupied after administration of both products. The hydrogel proved to be an excellent formulation in giving smaller inter-individual variation in penetration of Timolol into the aqueous humor. Only a weak correlation was seen between corneal thickness and the aqueous humor concentration of Timolol in the aqeuous 0.5% Timolol group. In conclusion, in contrast to the conventional aqueous 0.5% Timolol, 0.1% Timolol hydrogel caused only slight inter-individual variation in Timolol concentration in the aqueous humor.

  • Ophthalmic Timolol in a hydrogel vehicle leads to minor interindividual variation in Timolol concentration in aqueous humor
    Acta Ophthalmologica, 2008
    Co-Authors: Heikki Vapaatalo, Auli Ropo, Marjo Volotinen, J Mäenpää, H Kautiainen, A Tolonen, J Uusitalo, Esko Aine
    Abstract:

    Purpose Ophthalmic Timolol has been used for decades in the treatment of glaucoma and ocular hypertension, traditionally in aqueous 0.5% eye drops. Recently a Timolol 0.1% hydrogel has been developed to improve systemic safety. The aim of the present study was to compare aqueous humor Timolol concentrations after administration of 0.1% hydrogel and aqueous 0.5% Timolol in patients scheduled for a cataract operation. Results The concentration in the aqueous humor was 210 ± 175 ng/ml (mean ± SD) two hours after administration of Timolol 0.1% hydrogel and 538 ± 304 ng/ml after aqueous 0.5% Timolol. In the aqueous 0.5% Timolol group more patients had unnecessarily high concentrations of Timolol in the aqueous humor. Beta 1-receptors and Beta 2-receptors were practically 100% occupied after administration of both products. The hydrogel proved to be an excellent formulation in giving smaller inter-individual variation in penetration of Timolol into the aqueous humor. Only a weak correlation was seen between corneal thickness and the aqueous humor concentration of Timolol in the aqeuous 0.5% Timolol group. A similar correlation was observed between age and concentration of Timolol in the aqeuous 0.5% Timolol group. Conclusion In contrast to the conventional aqueous 0.5% Timolol, 0.1% Timolol hydrogel caused only slight inter-individual variation in Timolol concentration in the aqueous humor.

  • ophthalmic Timolol plasma concentration and systemic cardiopulmonary effects
    Scandinavian Journal of Clinical & Laboratory Investigation, 2007
    Co-Authors: Tuomo Nieminen, Hannu Uusitalo, Auli Ropo, Jukka Mäenpää, Terho Lehtimaki, Mika Kähönen
    Abstract:

    Timolol maleate is a non-selective beta-adrenoceptor antagonist currently used mainly as an ocular preparation for the treatment of glaucoma and ocular hypertension. Despite the topical administration, ophthalmic Timolol causes systemic adrenergic beta-blocking because of absorption from the eye into the systemic circulation. Gel formulations of ophthalmic Timolol have been developed to reduce systemic absorption and adverse effects in comparison with conventional aqueous solution formulations. Timolol is metabolized by the polymorphic cytochrome P450 2D6 enzyme (CYP2D6). The changes in heart rate (HR) are the most striking effects of the systematically absorbed fraction of ophthalmic Timolol, with 0.5 % aqueous formulations presenting larger effects than 0.1 % hydrogel formulations, especially during exercise. Plasma levels of ophthalmic Timolol correlate with the changes in HR. Neither 0.5 % aqueous nor 0.1 % hydrogel formulations of Timolol have exerted noteworthy effects on systolic (SAP) or diastolic (DAP) arterial pressures, probably because of a compensatory increase in systemic vascular resistance due to the attenuation of HR. Ophthalmic Timolol does not exert remarkable effects on pulmonary parameter peak expiratory flow (PEF) and forced expiratory volume in 1 s (FEV1) in non-asthmatic patients. CYP2D6 activity is clearly associated with the pharmacokinetic parameters, particularly when 0.5 % aqueous solution of Timolol is used: peak plasma concentration, elimination half-life and area-under-the-curve are highest in CYP2D6 poor metabolizers. Finally, since there is a correlation between the plasma level of Timolol and several haemodynamic effects - especially HR in the state of elevated beta-adrenergic tonus - the CYP2D6 poor metabolizers may be more prone to bradycardia during treatment with (aqueous) ophthalmic Timolol.

  • 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 archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie, 2006
    Co-Authors: Hannu Uusitalo, Mika Kähönen, Auli Ropo, Jukka Mäenpää, Gunilla Bjärnhall, Hans Hedenström, Väinö Turjanmaa
    Abstract:

    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. 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). 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. 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.