Three-month,randomized, parallel-group comparison of brimonidine–timolol versus dorzolamide–timolol fixed-combination therapy

ABSTRACT

Objective: Fixed combinations of 0.2% brimonidine–0.5% timolol and 2% dorzolamide–0.5% timolol are used to lower intraocular pressure (IOP). The objective of this study was to evaluate the IOP-lowering efficacy and ocular tolerability of brimonidine–timolol compared with dorzolamide–timolol when used as monotherapy or as adjunctive therapy to a prostaglandin analog (PGA) in patients with glaucoma or ocular hypertension.

Study design and methods: Pooled data analysis of two randomized, investigator-masked, 3-month, parallel-group studies with identical protocols (ten sites). In all, 180 patients with open-angle glaucoma or ocular hypertension who were in need of lower IOP received topical brimonidine–timolol BID or dorzolamide–timolol BID as monotherapy (n?=?101) or as adjunctive therapy to a PGA (latanoprost, bimatoprost, or travoprost) (n?=?79).

Clinical trial registration: The studies are registered with the identifiers NCT00822081 and NCT00822055 at http://www.clinicaltrials.gov.

Main outcome measures: IOP was measured at 10 a.m. (peak effect) at baseline and at months 1 and 3. Tolerability/comfort was evaluated using a patient questionnaire.

Results: There were no statistically significant between-group differences in patient demographics. Most patients were Caucasian, and the mean age was 68 years. There were also no statistically significant differences between treatment groups in baseline IOP. At month 3, the mean (SD) reduction from baseline IOP for patients on fixed-combination monotherapy was 7.7 (4.2) mmHg (32.3%) with brimonidine–timolol versus 6.7 (5.0) mmHg (26.1%) with dorzolamide–timolol (p?=?0.040). The mean reduction from PGA-treated baseline IOP for patients on fixed-combination adjunctive therapy was 6.9 (4.8) mmHg (29.3%) with brimonidine–timolol versus 5.2 (3.7) mmHg (23.5%) with dorzolamide–timolol (p?=?0.213). Patients on brimonidine–timolol reported less burning (p?<?0.001), stinging (p?<?0.001), and unusual taste (p?<?0.001) than patients on dorzolamide–timolol.

Conclusions: Fixed-combination brimonidine–timolol provided the same or greater IOP lowering compared with fixed-combination dorzolamide–timolol. Both fixed-combination medications were safe and well-tolerated. Brimonidine–timolol received higher ratings of ocular comfort than dorzolamide–timolol. The duration of the studies was 3 months, and additional studies will be needed to compare the efficacy and tolerability of brimonidine–timolol and dorzolamide–timolol during long-term treatment.     

Brimonidine-purite 0.1% versus brimonidine-purite 0.15% twice daily in glaucoma or ocular hypertension: a 12-month randomized trial*

ABSTRACT

Objective: To compare the safety and intraocular pressure (IOP)-lowering effects of brimonidine-purite^? 0.1% with the marketed formulation of brimonidine-purite 0.15% (Alphagan P^§ 0.15%) when used twice daily (BID) by patients with glaucoma or ocular hypertension previously treated with brimonidine-purite 0.15% for at least 6 weeks.

Methods: In a 12-month, randomized, double-masked, multicenter, parallel group, non-inferiority study, patients with glaucoma or ocular hypertension who were treated with brimonidine-purite 0.15% BID were randomly assigned to continue brimonidine-purite 0.15% (n = 102) or to administer brimonidine-purite 0.1% (n = 105) BID for 12 months. IOP was measured at approximately 8 a.m. (hour 0) and 10 a.m. (hour 2).

Main outcome measures: Mean change from baseline IOP and adverse events.

Results: Demographics and baseline characteristics were similar between treatment groups. Treated-baseline mean IOPs at both timepoints were similar between groups (p ≥ 0.606). Brimonidine-purite 0.1% provided IOP-lowering that was non-inferior to brimonidine-purite 0.15% at each of the 12 follow-up timepoints, and there were no statistically significant between-group differences at any timepoint. The most commonly reported adverse event was conjunctival hyperemia (13.5% for brimonidine-purite 0.1%; 10.8% for brimonidine-purite 0.15%). No significant differences in the incidence of adverse events were noted between the two formulations.

Conclusions: Brimonidine-purite 0.1% BID is as effective as brimonidine-purite 0.15% BID in lowering IOP in patients with glaucoma or ocular hypertension who were previously treated with brimonidine-purite 0.15%, and both formulations are well tolerated. Limitations of the study include enrollment of only patients who were already on treatment with brimonidine-purite 0.15%. The 0.1% formulation of brimonidine-purite allows for decreased exposure to brimonidine while providing an IOP-lowering effect comparable to that of the 0.15% formulation. Clinical trial registered at clinicaltrials.gov; identifier: NCT00168363.     

Brimonidine purite 0.1% versus brinzolamide 1% as adjunctive therapy to latanoprost in patients with glaucoma or ocular hypertension

ABSTRACT

Objective: To evaluate the efficacy and tolerability of brimonidine purite 0.1% in comparison to brinzolamide 1% when used as adjunctive therapy to latanoprost 0.005% in patients with glaucoma or ocular hypertension.

Methods: Randomized, single-center, investigator-masked, parallel-group clinical study. Patients with IOP?≥?18?mmHg while on once-daily latanoprost were randomized to adjunctive treatment with brimonidine purite TID (n?=?20) or brinzolamide TID (n?=?20) for 3 months. Intraocular pressure (IOP) was measured at 8 a.m., 10 a.m., and 4 p.m. at latanoprost-treated baseline and after 1 and 3 months of latanoprost and adjunctive therapy. A patient questionnaire was administered to evaluate the tolerability of eye drop instillation.

Results: Baseline mean diurnal IOP (± standard deviation, mmHg) on latanoprost was comparable between groups (brimonidine purite: 19.6?±?2.94; brinzolamide: 19.8?±?3.25; p = 0.846). Mean diurnal IOP at Month 3 was 16.3?±?2.63?mmHg with brimonidine purite and 17.8?±?2.19?mmHg with brinzolamide (?p = 0.028). Adjunctive use of brimonidine purite provided greater IOP lowering than brinzolamide at 10 a.m. (?p < 0.001) and 4 p.m. (?p = 0.050) and equivalent IOP lowering to brinzolamide at 8 a.m. (?p = 0.716). Blurred vision at Month 1 and bitter taste at Months 1 and 3 were more common upon instillation of brinzolamide eye drops.

Conclusion: Brimonidine purite 0.1% provided significantly lower IOP compared with brinzolamide 1% when used as adjunctive therapy to latanoprost. Both adjunctive therapies were well tolerated. Limitations of this study include the use of a single site and the sample size. Additional studies are needed to further evaluate these drugs as adjunctive therapy to prostaglandin analogs.     

Preservative-free versus preserved latanoprost eye drops in patients with open-angle glaucoma or ocular hypertension

Objective: This study compared the efficacy, safety, and pharmacokinetics of a preservative-free latanoprost formulation to an established, benzalkonium chloride (BAK) containing formulation for the treatment of open-angle glaucoma or ocular hypertension.

Methods: This was a phase II, randomized, cross-over, investigator-masked, multi-center, pilot study (NCT01494753). A total of 30 untreated adult patients (aged ≥18 years) with primary open angle glaucoma, pseudo-exfoliative glaucoma, pigmentary glaucoma, or ocular hypertension received either preservative-free or preserved latanoprost once daily in both eyes for 6 weeks, before crossing over to receive the other treatment. Efficacy (intraocular pressure [IOP] at 8 am, midday, 4?pm and 8?pm, and global efficacy assessment by investigator), safety (adverse events, ocular symptoms and global tolerance, slit lamp examination, funduscopy, visual field examination, visual acuity, and heart rate), and pharmacokinetics were assessed at Days 0, 42, and 84.

Results: Both treatments resulted in a reduction in IOP that was similar for the preservative-free and the preserved formulation at all time points. Similarly, the overall diurnal reduction was similar in both groups (6.3?mmHg [27.9% reduction] and 6.4?mmHg [28.1% reduction] for preserved and preservative-free latanoprost, respectively). There were no differences in global efficacy assessment or in the safety and tolerance of each treatment. Systemic concentrations of latanoprost were very low; AUC_0–30 and C_max were lower and t_max was longer for preservative-free latanoprost.

Conclusions: Preservative-free latanoprost showed similar efficacy at all time points compared to BAK preservative containing formulation, with no difference in tolerance, allowing progression to phase III clinical development.     

Comparison of allergy rates in glaucoma patients receiving brimonidine 0.2% monotherapy versus fixed-combination brimonidine 0.2%–timolol 0.5% therapy

ABSTRACT

Objective: To evaluate the incidence of ocular allergy in glaucoma patients prospectively treated with 0.2% brimonidine–0.5% timolol fixed combination (Combigan) compared with the incidence of ocular allergy in patients treated with 0.2% brimonidine (Alphagan?) monotherapy.

Study design and methods: This was a comparative, non-randomized, single-site, interventional study involving patients with primary open-angle glaucoma or exfoliation syndrome who had not previously used brimonidine in any formulation and had no history of ocular allergy. In one study arm, 102 patients were prospectively treated with twice-daily 0.2% brimonidine–0.5% timolol fixed combination. In the other study arm, medical charts at the same center were reviewed to identify a control group of 102 patients who had been treated with twice-daily 0.2% brimonidine monotherapy. Follow-up was at 1, 3, 6, 9, 12, 15, and 18 months of treatment.

Main outcome measure: Ocular allergy defined as the presence of follicles and redness severe enough to warrant discontinuation of the medication.

Results: The incidence of ocular allergy over 18 months of treatment was 8.8% (9/102) in the fixed-combination group compared with 17.6% (18/102) in the brimonidine group (?p?=?0.097). Kaplan–Meier survival analysis suggested that ocular allergy may be reduced or delayed in patients treated with the brimonidine–timolol fixed combination (?p?=?0.066).

Conclusions: The brimonidine–timolol fixed combination was associated with a 50% lower incidence in ocular allergy compared with 0.2% brimonidine monotherapy. This difference between treatments was not statistically significant (?p?=?0.097) but is likely to be clinically important. Additional studies are needed to evaluate the incidence of ocular allergy associated with brimonidine–timolol fixed combination treatment.     

Efficacy and safety of brimonidine and dorzolamide for intraocular pressure lowering in glaucoma and ocular hypertension

ABSTRACT

Background: Brimonidine and dorzolamide are intraocular pressure (IOP)-lowering medications most commonly used in second-line treatment of glaucoma and ocular hypertension.

Scope: An evidence-based review of comparative clinical trials of brimonidine and dorzolamide was undertaken to determine the relative efficacy and safety of these drugs in reducing IOP. Using the keywords ‘brimonidine’ and ‘dorzolamide’, all articles describing such trials from September 1966 to July 2007 were found in MEDLINE and EMBASE.

Findings: In all identified studies, brimonidine and dorzolamide were both found to provide significant IOP reduction from treated or untreated baseline levels. Results of eight trials reported to date indicate that brimonidine produced either a lower treated IOP or greater pressure reduction from baseline than dorzolamide at one or more measured timepoints, and provided comparable IOP lowering over all other measurements. Differences between the IOP reductions provided by brimonidine and dorzolamide were more pronounced when the medications were used adjunctively with other classes of drugs. Six other trials showed similar efficacy, and one additional monotherapy study showed lower IOP with dorzolamide treatment. Ocular burning was noted with dorzolamide more than any other adverse event with either drug. Trials ranged widely in duration of therapy and the time of day IOP measurements were taken, and many were too small for sufficient statistical power.

Conclusion: Brimonidine and dorzolamide are both efficacious and reasonably well tolerated. Possible overall distinctions in efficacy were obscured by differences in study designs and treatment regimens, but adjunctive therapy with brimonidine may reduce IOP as effectively or more effectively than adjunctive or fixed combination dorzolamide therapy. In certain patients with glaucoma and ocular hypertension brimonidine may be a better choice than dorzolamide for second-line treatment.     

Treatment of patients with primary open-angle glaucoma with a fixed combination of brimonidine 0.2%/timolol 0.5%: multicenter,open-label,observational study in Germany*

ABSTRACT

Objective: At the introduction of the fixed-combination of brimonidine/timolol in Germany in 2006, a non-interventional, multicenter, observational, open-label study was initiated to evaluate efficacy, tolerability, and safety of this preparation in a broad patient population.

Methods: The study population comprised patients with bilateral primary open-angle glaucoma or ocular hypertension with insufficient intraocular pressure (IOP) control who participating physicians determined required a change of medication, and who switched to exclusive use of the new fixed-combination brimonidine 0.2%/timolol 0.5%. Patient demographics and information on specific risk factors were collected. IOP readings were recorded for each eye at treated baseline (previous therapy), 4 to 6 weeks, and 12 weeks after changing to twice-daily brimonidine/timolol. Tolerability was measured using a four-step scale ranging from excellent to poor. All adverse events were recorded.

Results: Mean treated baseline IOP (±SD) for all patients (N?=?861) was 20.8?±?3.5?mmHg. Five hundred sixty-five patients switched from monotherapy, 138 patients switched from other fixed combinations, and 158 patients had been using non-fixed combinations of up to four different active agents. The brimonidine/timolol fixed combination provided an additional IOP decrease in most pretreatment subgroups, with an overall reduction to 16.9?±?2.6?mmHg after 4 to 6 weeks and to 16.5?±?2.7?mmHg after 12 weeks. Both of these values were significantly lower than baseline IOP (p?<?0.001). A target pressure of <18?mmHg was achieved in 79.5% of all eyes at week 12. Tolerability of fixed-combination brimonidine/timolol was rated excellent or good by the physicians for 97.1% of patients, and by 93.4% of the patients themselves. Few adverse events occurred during the treatment period.

Conclusions: Although this study was limited by its observational design, our results show that the fixed combination of brimonidine 0.2%/timolol 0.5% was effective, well tolerated, and safe in a broad POAG patient population.     

Brimonidine and brinzolamide for treating glaucoma and ocular hypertension; a safety evaluation

Introduction: Brimonidine tartrate and brinzolamide eye drops are often used as third and fourth line treatment options to reduce intraocular pressure (IOP) in the management of glaucoma and ocular hypertension. Better tolerated, more effective topical agents requiring once daily instillation including prostaglandin analogues and beta-blockers usually are preferred as initial therapy, unless there are contraindications. Brimonidine and brinzolamide are often required owing to progressive glaucoma or intolerances to or ineffectiveness of front-line agents.

Areas covered: We review the safety of formulations containing brimonidine tartrate and/or brinzolamide. Safety considerations for these agents in higher risk populations are highlighted.

Expert opinion: Each class of ocular hypotensive eye drop has a unique set of possible side effects. Brimonidine might have neuro-protective capabilities and offer reasonable IOP control, but its use is limited by a relatively high rate of ocular allergy, hyperemia and discomfort. Brinzolamide is generally well tolerated, but often lacks efficacy. The introduction of brimonidine/brinzolamide fixed combination suspension improves adherence (by simplifying the medical regimen) and reduces preservative load on the ocular surface. New drug delivery systems incorporating brimonidine and brinzolamide are in development and promise to improve the safety profiles of both drugs.     

Changes in intraocular pressure following a switch from latanoprost monotherapy to latanoprost/timolol fixed combination therapy in patients with primary open-angle glaucoma or ocular hypertension: results from a clinical practice database

ABSTRACT

Aims: To assess the incremental change in intraocular pressure (IOP) levels in patients with primary open-angle glaucoma or ocular hypertension, insufficiently treated with topical ocular hypotensive monotherapy or combination therapy and changed to the latanoprost/timolol fixed-combination therapy (LTFC).

Methods: The glaucoma database of the Glasgow Royal Infirmary was reviewed retrospectively to identify patients ≥?18 years of age with primary open-angle glaucoma or ocular hypertension in at least one eye who had been switched to LTFC from a previous monotherapy or combination therapy. Ninety patients were identified, and 59 (66%) had changed to LTFC from latanoprost monotherapy (LM). The analysis focused on this subgroup because few patients were changed from any other single therapy. At least one documented patient visit following the change to LTFC was required. The within-subject difference in IOP levels (IOP on LM–IOP on LTFC) was calculated for each case, and the statistical significance of the mean change in IOP was analysed using a 2-sided Student's paired t-test with a 0.05 α level.

Results: The mean decrease in IOP after changing to LTFC from LM was 2.6?mmHg (95% confidence interval?=?1.6, 3.6), from 21.4 (SD?=?3.5) mmHg to 18.8 (SD?=?4.2) mmHg (p?=?0.002).

Conclusions: LTFC provides significant incremental IOP reduction in patients with primary open-angle glaucoma or ocular hypertension who require additional IOP reduction following treatment with LM.     

Tolerability of loteprednol/tobramycin versus dexamethasone/tobramycin in healthy volunteers: results of a 4-week,randomized, double-masked,parallel-group study

ABSTRACT

Objective: To compare the ocular comfort and tolerability of loteprednol etabonate 0.5%/tobramycin 0.3% (LE/T; Zylet^*) with dexamethasone 0.1%/tobramycin 0.3% (DM/T; TobraDex^?) in healthy volunteers.

Research design and methods: In this multicenter, randomized, double-masked, parallel-group study, healthy volunteers (n?=?306) were randomized to receive LE/T or DM/T four times per day for 28 days. Subjects recorded subjective ratings for seven comfort/tolerability parameters using an electronic patient diary (EPD). The primary endpoint was the difference at week 4 from the ratings of an artificial tear at baseline in comfort/tolerability parameters between treatment groups, using a noninferiority paradigm.

Clinical trials registration: ClinicalTrials.gov, NCT 00532961.

Results: The 97.5% confidence intervals for the lower bound were within –10 for all of the seven comfort/tolerability parameters evaluated (pain, stinging/burning, irritation, itchiness, foreign-body sensation, dryness, and light sensitivity). Secondary analysis revealed small but significant within-treatment differences in pain favoring LE/T over tears and in light sensitivity favoring tears over DM/T (p?<?0.01). Small between-treatment differences in the changes from baseline tear ratings to individual study visits favored LE/T for pain, stinging/burning, irritation, itchiness, foreign-body sensation, and light sensitivity at visit 4 (p?≤?0.04); for pain, stinging/burning, and foreign-body sensation at visit 5 (p?≤?0.03), and for dryness and light sensitivity at visit 6 (p?≤?0.05).

Conclusions: LE/T satisfied all conditions of noninferi-ority to DM/T in comfort and tolerability. Subjects receiving LE/T were more likely to report better ocular comfort/tolerability ratings relative to baseline artificial tears than subjects receiving DM/T.

Limitations: The study population consisted of healthy volunteers.     

Mechanism - Based Translational Pharmacokinetic - Pharmacodynamic Model to Predict Intraocular Pressure Lowering Effect of Drugs in Patients with Glaucoma or Ocular Hypertension

Purpose

To develop a mechanism based translational pharmacokinetic-pharmacodynamic (PKPD) model in preclinical species and to predict the intraocular pressure (IOP) following drug treatment in patients with glaucoma or ocular hypertension (OHT).

Methods

Baseline diurnal IOP of normotensive albino rabbits, beagle dogs and patients with glaucoma or OHT was collected from literature. In addition, diurnal IOP of patients treated with brimonidine or Xalatan® were also obtained from literature. Healthy normotensive New Zealand rabbits were topically treated with a single drop of 0.15% brimonidine tartrate and normotensive beagle dogs were treated with a single drop of Xalatan®. At pre-determined time intervals, IOP was measured and aqueous humor samples were obtained from a satellite group of animals. Population based PKPD modeling was performed to describe the IOP data and the chosen model was extended to predict the IOP in patients.

Results

Baseline IOP clearly depicts a distinctive circadian rhythm in rabbits versus human. An aqueous humor dynamics based physiological model was developed to describe the baseline diurnal IOP across species. Model was extended to incorporate the effect of drug administration on baseline IOP in rabbits and dogs. The translational model with substituted human aqueous humor dynamic parameters predicted IOP in patients following drug treatment.

Conclusions

A physiology based mechanistic PKPD model was developed to describe the baseline and post-treatment IOP in animals. The preclinical PKPD model was successfully translated to predict IOP in patients with glaucoma or OHT and can be applied in assisting dose and treatment selection and predicting outcome of glaucoma clinical trials.     

Efficacy and ocular surface tolerability of preservative-free tafluprost 0.0015%: a 6-month,single-blind,observational study on naïve ocular hypertension or glaucoma patients

Objectives: The aim of this study was to evaluate the safety of preservative-free tafluprost in newly diagnosed patients and to confirm its efficacy in lowering intraocular pressure (IOP).

Methods: Naïve patients were submitted to an ophthalmic examination, including ocular surface status and quality of life evaluation. All examinations were performed at baseline and after 1 and 6 months.

Results: 28 patients were enrolled and treated with tafluprost, once a day, in the evening. TF-BUT changed from 9 (interquartile range (IQR) 6 – 11) s at baseline to 10 (IQR 7 – 10) s at 1 month (p = 0.106) and 9 (IQR 6 – 12) s at 6 months (p = 0.003). No eye developed corneal staining. Quality of life was (median (IQR)) 91.6 (79.2 – 95.8) at baseline and 95.8 (66.7 – 100) at 6 months (p = 0.62). Only a few adverse events occurred during the follow-up period (three patients experienced ocular burning and one developed redness). The mean IOP reduction was 5.5 mm Hg (95% CI 3.8 – 7.2). The median (IQR) baseline IOP was 18.7 (15 – 23.7) mm Hg; 14 (13 – 16) mm Hg and 16 (14 – 16) mm Hg (p < 0.0001) after 1 and 6 months, respectively.

Conclusion: No patient developed ocular surface disease and quality of life perception was preserved. Preservative-free tafluprost is therefore an effective drug that is safe for the ocular surface after 6 months of daily therapy.     

Development,in vitro and in vivo characterization of Eudragit RL 100 nanoparticles for improved ocular bioavailability of acetazolamide

Abstract

Glaucoma is characterized by increased intra ocular pressure (IOP) which results in blindness if left untreated. Acetazolamide (ACZ) is used to treat glaucoma since long back. Since it is a Class IV drug [According to Biopharmaceutics Classification System (BCS)], so its topical delivery results in poor ocular bioavailability. Objective of the present study is to increase the topical ocular bioavailability and to sustain the release of drug for longer time. ACZ-loaded Eudragit® RL 100 nanoparticle suspension (ACZ-E-NPs) was prepared by the nanoprecipitation method. Ratio of organic to aqueous phase and composition of organic phase were altered to get the best formulation. Formulations prepared with acetone and methanol as organic phase were smallest in size. EE was in the range of 57.8% to 68.5%. According to drug release study almost all the formulations released 80% of drug in 8?h duration. The kinetics of drug release showed that the drug release pattern followed Higuchi’s model (highest R² values) and further it was fitted to the Korsemeyer–Peppas model, which showed the release was as per Fickian diffusion. IOP lowering effects of plain drug solution and ACZ-E-NPs were compared in adult male albino rabbits with a Riester Tonometer. The data revealed that the ACZ-E-NPs lower the IOP for longer time and of higher magnitude also. The difference was significant (p?<?0.001). Short-term stability study showed that none of the formulations was having remarked difference in their physicochemical properties after 6 months of storage at various temperatures.     

Comparing bimatoprost and travoprost in black Americans

ABSTRACT

Objective: To compare the intraocular pressurelowering efficacy and safety of topical bimatoprost 0.03% with that of travoprost 0.004% for the reatment of black patients with open-angle glaucoma (OAG) and ocular hypertension (OHT).

Research design and methods: Multicenter, prospective, randomized, investigator-masked trial of 94 black patients previously diagnosed with OAG or OHT. All patients completed washout of ocular hypotensive medications before study participation. Patients were assigned to either once-daily bimatoprost 0.03% or once-daily travoprost 0.004% for 3 months.

Main outcome measures: The primary outcome measures were mean intraocular pressure (IOP), mean change from baseline IOP, and percentage of patients who reached a target IOP reduction. Secondary measures included ophthalmologic examination and adverse events.

Results: Both bimatoprost and travoprost significantly lowered IOP at all study visits (?p < 0.001). Bimatoprost provided mean IOP reductions from baseline that ranged from 6.8?mmHg to 7.8?mmHg (27% to 31%). Travoprost provided mean IOP reductions from baseline that ranged from 6.2?mmHg to 6.9?mmHg (25% to 28%). By month 3, 85% of participants in the bimatoprost group had a mean IOP reduction of at least 20%, compared with 68% of those in the travoprost group. Furthermore, 31.9% of those in the bimatoprost group had a mean IOP reduction of more than 40% at month 3 compared with 20.9% of those in the travoprost group. There were no significant differences in biomicroscopy, ophthalmoscopy, or visual acuity. Ocular redness was the most commonly reported adverse event in both treatment groups. No serious adverse events were reported.

Conclusions: Bimatoprost and travoprost each effectively lowered IOP in this population of black patients. More patients achieved clinically relevant IOP reductions with bimatoprost.     

Chick chorioallantoic membrane model for in ovo evaluation of timolol maleate–brimonidine tartrate ocular inserts

Abstract

The main aspire of this study was to develop ocular drug delivery system for dual drug glaucoma therapy by timolol maleate–brimonidine tartrate and endeavor the possibility of biocompatibility studies by in ova studies. Matrix type, both hydrophilic and lipophilic polymers, and reservoir-type ocular inserts of timolol maleate were prepared using hydrophilic polymers like polyvinyl alcohol, hydroxyl propyl methyl cellulose K4M and lipophilic polymers like ethylcellulose and eudragit S100 and were optimized. Based on the optimized formulation, triple-layered ocular inserts (reservoir type) of dual drug were prepared by solvent casting technique with an objective of reducing the frequency of administration, obtaining controlled release and greater therapeutic efficacy, preservative free dosage form for the treatment of glaucoma. FTIR spectral studies revealed no pharmaceutical incompatibility and no drug polymer interactions. Maximum drug release (99.18?±?1.7) was achieved when PVP and HPMC K4M in 1:1 ratio with PEG 400 (0.3?ml) drug reservoir layer was sandwiched between ethyl cellulose as rate control membrane up to 32?h in a controlled fashion. Drug release was by non-Fickian diffusion mechanism for single drug formulation. But in dual drug insert, timolol maleate best fit into zero order and for brimonidine tartrate to Higuchi model and diffusion of drugs from this by non-Fickian diffusion mechanism. In ovo studies suggested that the optimized formulation was found to be sterile, biocompatible and physicochemically stable and support us to claim that the developed formulation was biocompatible.     

A meta-analysis of topical prostaglandin analogues intra-ocular pressure lowering in glaucoma therapy

ABSTRACT

Objective: To compare the ef?cacy of latanoprost, bimato­prost and travoprost for lowering IOP in patients with glaucoma.

Research design and methods: In order to carry out this meta-analysis, randomized trials (2001–2004) were identi?ed on Medline and EMBASE using the following key words: glaucoma, ocular hypertension (OHT), random­ization, trial, latanoprost, bimatoprost and travoprost. The studies had to compare at least two prostaglandin analogues as mono-therapy. Cross-over experimental designs were excluded. The main outcome measure was IOP at ?nal visit. Statistical analyses included random effects, pooled estimates of treatment effects, tests for publication bias, and random-effects models to obtain adjusted treatment effects on ?nal IOP after lowering for baseline IOP, and duration of follow-up. Random effects Poisson regression models were used to estimate the adjusted effects of treatments on response rates (IOP < 18?mmHg).

Results: Nine studies were used in the analysis. Patient mean age varied from 56.7 to 68.8 years and baseline IOP ranged from 22.3 to 26.5?mmHg. Three hundred and seventy-eight patients were treated with bimatoprost, 385 with travoprost and 555 with latanoprost. Patients treated with travoprost and bimatoprost had lower IOP levels at the end of follow-up (–0.98?mmHg [95% CI: –2.08; 0.13; p = 0.08] and –1.04?mmHg [95% CI: –2.11;0.04; p = 0.06], respectively) than those treated with latanoprost. The combined effect of newer prostaglandin analogues (bimatoprost/travoprost) was an adjusted decrease of 1.00?mmHg [95% CI: –1.91;–0.10], p = 0.03], or a 17% higher adjusted response rate (Incidence Rate Ratio 1.17, 95% CI, 1.00–1.35, p = 0.04), compared to latanoprost.

Conclusion: Travoprost and bimatoprost may have greater ef?cacy in lowering IOP for patients with OHT or glaucoma.     

Efficacy,tolerability and safety of the fixed combination of bimatoprost 0.03% and timolol 0.5% in a broad patient population: multicenter,open-label observational study*

ABSTRACT

Objective: To evaluate intraocular pressure (IOP)-lowering efficacy, tolerability, and safety of the fixed combination of bimatoprost 0.03% and timolol 0.5% (Ganfort^?) among German patients.

Methods: Multicenter, observational, open-label study of patients with primary open angle glaucoma or ocular hypertension (n?=?606). As determined by participating physicians, patients had insufficient IOP control and required a medication change. They were switched to once-daily fixed-combination bimatoprost/timolol with no wash-out period. IOP was recorded at treated baseline, 4–6 weeks and 12 weeks after switching. Tolerability was measured using a 4-step scale (excellent, good, moderate, poor) and all adverse events were recorded.

Results: A total of 405 patients switched from monotherapy, 97 switched from other fixed combinations, and 104 switched from non-fixed combinations. Among all patients, 32.5% had used prostaglandin analog (PGA) monotherapy, 8.7% had been using a fixed combination that included a PGA, and 6.9% had been using an adjunctive combination of a PGA and a β-blocker. Mean treated baseline IOP (±SD) for all patients was 20.7?±?3.5?mmHg. Overall, changing medication to fixed-combination bimatoprost/timolol lowered IOP to 16.6?±?2.7?mmHg (p?<?0.001 vs. baseline) after 4–6 weeks and to 16.1?±?2.6?mmHg (p?<?0.001) after 12 weeks; reductions of 19.8% and 22.2%, respectively. Combined bimatoprost/timolol provided an additional IOP reduction versus baseline in most subgroups based on prior treatment. At week 12, patients who had previously used a β-blocker achieved an additional 25.8% decrease from baseline and IOP was reduced by 22.6% in former PGA monotherapy patients. At week 12, 84.6% of all eyes reached a target pressure less than or equal to 18?mmHg. Tolerability of bimatoprost/timolol was rated excellent or good by the physicians for 98.7% of patients and by 96.7% of the patients themselves. Few adverse events occurred during the treatment period.

Conclusions: Although this study was limited by its observational design, our results show that the fixed combination of bimatoprost 0.03%/timolol 0.5% was effective, well tolerated, and safe in a broad patient population.     

Intraocular pressure reduction with travoprost/timolol fixed combination,with and without adjunctive brinzolamide,in glaucoma

ABSTRACT

Objective: To investigate if combined intraocular pressure (IOP)-lowering medication with travoprost/timolol fixed combination and a carbonic anhydrase inhibitor, brinzolamide, is superior to both travoprost monotherapy and travoprost/timolol fixed-combination therapy in primary open-angle glaucoma and ocular hypertension.

Methods: Following a 4-week wash-out period and using 4-week long treatment periods, 20 primary open-angle glaucoma or ocular hypertension patients were treated with evening travoprost 0.004?%?, then switched to evening travoprost 0.004?%?/timolol 0.5?%?fixed combination, and finally the treatment was combined with adjunctive twice-daily brinzolamide 1?%?ophthalmic suspension. Both eyes were treated, but only one eye per patient (the eye with the higher mean diurnal IOP at baseline), was evaluated. IOP was measured at 8 a.m., 12 noon and 4 p.m. at baseline and at the end of each treatment period.

Results: Mean diurnal IOP (mean (SD)) at baseline was 28.5 (7.3) mmHg which decreased to 22.3 (6.3) mmHg on travoprost, 19.2 (3.4) mmHg on travoprost/timolol fixed combination and 17.3 (3.4) mmHg when the brinzolamide was added to the travoprost/timolol combination (ANOVA, contrast test, p?<?0.003 for all comparisons). The individual time point IOP values showed similar and significant stepwise differences.

Conclusion: Adjunctive brinzolamide medication provided further IOP decrease in patients receiving evening-dosed travoprost/timolol fixed combination. The travoprost/timolol fixed combination was significantly more effective in IOP reduction than travoprost monotherapy, which by itself induced a significant IOP decrease compared to the untreated baseline value. The results of this open label study suggest that combined therapy with travoprost/timolol fixed combination and brinzolamide is clinically useful for IOP-lowering in primary open-angle glaucoma and ocular hypertension.     

国产与进口溴莫尼定滴眼液的多中心临床对照试验139例

目的:验证国产溴莫尼定滴眼液治疗原发性开角型青光眼和高眼压症的治疗价值。方法:对139例原发性开角型青光眼及高眼压症病人进行为期6 wk的多中心、随机、双盲、阳性对照研究,试验组滴用国产制剂,对照组滴用进口制剂,均早、晚各1次,于治疗前,治疗后2,4,6 wk,随访眼压的变化,并做眼部检查、视野检查,观察生命体征和不良反应。结果:试验组入选70例(70只眼),对照组入选69例(69只眼),完成试验的分别为60例(60只眼)和61例(61只眼)。6 wk后试验组眼压下降(1.0±s0.5)kPa,降眼压的有效率(眼压下降>10%)为98%;对照组下降(0.9±0.4)kPa,有效率为100%。2组比较差异无显著意义。部分病人出现眼烧灼感、眼刺痛、口干、疲劳等不适症状,除试验组2例病人因此中止试验外,其余均能良好耐受。结论:国产溴莫尼定滴眼液对于控制原发性开角型青光眼和高眼压症的眼压是有效和安全的,效果与进口制剂相当。     

Comparison of the efficacy and safety of travoprost with a fixed-combination of dorzolamide and timolol in patients with open-angle glaucoma or ocular hypertension

ABSTRACT

Purpose: The purpose of this study was to compare travoprost (TRAV; travoprost 0.004%) and the fixed-combination of dorzolamide/timolol (DTFC; dorzolamide 2.0%/timolol maleate 0.5%) ophthalmic solutions for reducing intraocular pressure (IOP) in patients with primary open-angle glaucoma (OAG) or ocular hypertension (OHT).

Methods: This was a randomized single masked, study with parallel controls. The TRAV group (n = 29) dosed once daily at 9:00 PM while the DTFC group (n = 27) dosed twice daily at 9:00 AM and 9:00 PM. IOP was measured at baseline, and following 3 weeks and 6 weeks of treatment at 8:00 AM, 12:00 PM, 4:00 PM, and 8:00 PM.

Results: Mean average IOP reductions from baseline during the course of the day were 7.5 (32.7%) and 7.1 (30.7%)?mmHg for TRAV and 4.8 (23.1%) and 4.5 (21.7%)?mmHg for DTFC at 3 weeks and 6 weeks, respectively. The greater IOP reduction for patients receiving TRAV was statistically significant at both the 3 and 6 week visits when averaged across all four time points (?p < 0.01). The two products were well-tolerated over the course of the 6 week study. Some factors such as taste perversion were reported more often in the DTFC group.

Conclusions: Travoprost monotherapy provided better efficacy in terms of IOP reduction and per-centage of IOP reduction compared to dorzolamide 2.0%/timolol maleate 0.5% fixed combination.