Topical dorzolamide 2%/timolol 0.5% ophthalmic solution: a review of its use in the treatment of glaucoma and ocular hypertension

Topically administered dorzolamide 2%/timolol 0.5% (dorzolamide/timolol ophthalmic solution; Cosopt) is a fixed combination of two ocular hypotensive drugs (the carbonic anhydrase inhibitor dorzolamide and the beta-adrenoceptor antagonist timolol) that have an additive effect on lowering intraocular pressure (IOP) when administered together. This product is indicated for the treatment of elevated IOP in patients with open-angle glaucoma or ocular hypertension (OH) who are insufficiently responsive to topical beta-adrenoceptor antagonist monotherapy. As such, it can be considered for use in individuals who, as a consequence of failing to achieve target IOP with beta-adrenoceptor antagonist monotherapy, require the addition or substitution of another class of topical antiglaucoma medication. Clinical trials have demonstrated that dorzolamide/timolol (1 drop per eye twice daily) is an effective and generally well tolerated fixed combination for lowering IOP in patients with open angle glaucoma or OH, including individuals uncontrolled on beta-adrenoceptor antagonist monotherapy. Compared with concomitant therapy with the individual components, the primary advantage of fixed combination dorzolamide/timolol is convenience.     

Topical dorzolamide 2%/timolol 0.5%: a review of its use in the treatment of open-angle glaucoma

The nonselective beta-blocker timolol and the carbonic anhydrase inhibitor dorzolamide both lower intraocular pressure (IOP). Timolol and dorzolamide have different mechanisms of action and their effects are additive when administered together. Therefore, the 2 drugs are frequently used concomitantly to treat patients with open-angle glaucoma who have not adequately responded to first-line therapy. A barrier to good compliance with concomitant therapy is the need to administer 5 or 6 drops of medication on 2 or 4 occasions during the day. Timolol 0.5% and dorzolamide 2.0% have therefore been combined in a single formulation, reducing the number of administrations required to 2 per day. Clinical trials in patients with glaucoma have demonstrated that dorzolamide 2%/timolol 0.5% (dorzolamide/timolol) is superior to monotherapy with the individual components. When dorzolamide/timolol administered twice daily was compared with concomitant treatment with dorzolamide 2% and timolol 0.5%, each administered twice daily for 90 days, both regimens resulted in marked lowering of trough IOP (measured just before the morning dose) compared with baseline (reduction in IOP = 4.2mm Hg). The effect of the 2 regimens on IOP at all time points, both before treatment and at peak effect (2 hours after treatment), were virtually indistinguishable. When the combined formulation was compared with a concomitant regimen that included dorzolamide 2% 3 times daily and timolol 0.5% twice daily the concomitant regimen was slightly more efficacious than the combined regimen at trough after 90 days: IOP was lowered by 3.6mm Hg in the combined group versus 4.1 mm Hg in the concomitant group. Dorzolamide/timolol has been compared with concomitant administration of timolol 0.5% and the IOP lowering miotic drug, pilocarpine 2.0%. This non-blind patient-preference study found that both regimens reduced IOP. However, the dorzolamide/timolol combination was preferred by the patients because of reduced frequency and severity of adverse effects and less frequent administration. Dorzolamide/timolol was well tolerated in clinical trials, the adverse effects reflected those of the individual components, and no additional tolerability issues were identified. However, the potential for timolol to cause cardiorespiratory effects must be considered when prescribing this combination. Furthermore, dorzolamide is a sulfonamide and can cause allergic reactions in those who are hypersensitive to this class of drug. CONCLUSIONS: Dorzolamide/timolol is a well tolerated and effective fixed combination for lowering IOP in the treatment of open-angle glaucoma and is likely to be useful in those patients who do not respond adequately to first-line monotherapy. Compared with concomitant therapy with the same 2 drugs the primary advantage is convenience, which may lead to improved compliance. Studies of compliance and comparisons with other currently available combination therapies would be useful to fully define the value of the formulation. Nonetheless, dorzolamide combined with timolol in a single applicator system will be a useful addition to the treatment options for glaucoma, a leading cause of preventable blindness.     

Latanoprost : an update of its use in glaucoma and ocular hypertension

Latanoprost (Xalatan) is an ester analogue of prostaglandin F2alpha that reduces intraocular pressure (IOP) by increasing uveoscleral outflow. The IOP-lowering efficacy of latanoprost 0.005% lasts for up to 24 hours after a single topical dose, which allows for a once-daily dosage regimen. In patients with ocular hypertension or open-angle glaucoma, a single drop of latanoprost 0.005% solution (about 1.5 microg) administered topically once daily reduced diurnal IOP by 22 to 39% over 1 to 12 months' treatment in well-controlled trials; efficacy was maintained during treatment periods of up to 2 years. At this dosage, latanoprost was significantly more effective than timolol 0.5% twice daily in 3 of 4 large, double-blind, randomised studies, was generally as effective as bimatoprost or travoprost, and was significantly more effective than dorzolamide, brimonidine or unoprostone. Furthermore, in patients whose IOP was poorly controlled with timolol, switching to latanoprost monotherapy was at least as effective at lowering IOP as adding dorzolamide or pilocarpine to the regimen. Latanoprost has also shown significant additive effects when used in combination with one or more other glaucoma medications. The fixed combination of latanoprost plus timolol was significantly more effective than either of its individual components in two double-blind randomised studies and more effective than the fixed combination of dorzolamide and timolol in a 3-month, evaluator-masked study. Data in patients with angle-closure glaucoma are limited, but in patients with elevated IOP after undergoing iridotomy, latanoprost 0.005% once daily was significantly more effective than timolol 0.5% twice daily at reducing IOP over 12 weeks of treatment in a large double-blind, randomised study. Latanoprost is generally well tolerated and, unlike timolol, induces minimal systemic adverse events. In well-controlled, 6-month trials, the most commonly occurring drug-related ocular events in latanoprost recipients were mild to moderate conjunctival hyperaemia (3 to 15%) and iris colour change (2 to 9%); these seldom required patient withdrawal although the latter may be permanent. Latanoprost 0.005% as a single daily drop has shown good IOP-lowering efficacy in patients with open-angle glaucoma or ocular hypertension and does not produce the cardiopulmonary adverse effects associated with beta-blockers. Thus, latanoprost is a valuable addition to the first-line treatment options for patients with open-angle glaucoma or ocular hypertension. In addition, adjunctive treatment with latanoprost in patients who are refractory to beta-blocker therapy is a viable, second-line treatment option. Although preliminary findings are promising, wider clinical experience is required to define the place of latanoprost in the treatment of angle-closure glaucoma.     

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.     

Brinzolamide : a review of its use in the management of primary open-angle glaucoma and ocular hypertension

Brinzolamide is a highly specific carbonic anhydrase (CA) inhibitor which lowers intraocular pressure (IOP) by reducing the rate of aqueous humour formation. Formulated as a 1% ophthalmic suspension (Azopt) and administered twice or three times daily, brinzolamide is indicated for the topical management of primary open-angle glaucoma (POAG) and ocular hypertension (OH) as either monotherapy or adjunctive therapy with topical beta-blockers. As monotherapy in patients with POAG or OH, brinzolamide 1% demonstrated IOP-lowering efficacy that was significantly greater than placebo, equivalent to three-times-daily dorzolamide 2% but significantly lower than twice-daily timolol 0.5%. Brinzolamide 1% was equally effective in twice- and three-times-daily regimens producing diurnal mean IOP reductions from baseline in the range of 13.2-21.8%. When used adjunctively twice daily with timolol 0.5%, brinzolamide 1% was as effective as dorzolamide 2% and superior to placebo in lowering IOP in patients with POAG or OH. In clinical trials, brinzolamide 1% was well tolerated causing only nonserious adverse effects that were generally local, transient and mild to moderate in severity. The incidence of the most common adverse events associated with the use of brinzolamide 1% was either similar to (blurred vision and abnormal taste) or significantly lower than (ocular discomfort) with dorzolamide 2%. Topical brinzolamide 1% does not appear to produce the acid-base or electrolyte disturbances and severe systemic adverse effects characteristic of oral CA inhibitors. It can be used in patients unresponsive to beta-blockers or in whom beta-blockers are contraindicated. Brinzolamide 1% administered twice daily is among the least costly alternatives and adjuncts to beta-blocker therapy for glaucoma and is generally associated with less direct medical cost than dorzolamide. CONCLUSION: Brinzolamide 1% ophthalmic suspension administered twice or three times daily, as monotherapy or adjunctive therapy with topical beta-blockers, has good IOP-lowering efficacy in patients with POAG or OH that is equivalent to that of dorzolamide 2% (three times daily as monotherapy, twice daily as adjunctive therapy). Brinzolamide is generally well tolerated and does not produce the systemic adverse effects associated with oral CA inhibitors. It can be used in patients who are unresponsive to, intolerant of, or unable to receive, ophthalmic beta-blockers. Thus, brinzolamide, either as monotherapy or adjunctive therapy with topical beta-blockers, should be regarded as a good second-line option in the pharmacological management of POAG and OH, and may be preferred over dorzolamide because of significantly less ocular discomfort.     

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.     

Brinzolamide/timolol fixed combination: a new ocular suspension for the treatment of open-angle glaucoma and ocular hypertension

For the treatment of open-angle glaucoma, the most frequent cause of irreversible visual loss, fixed combinations of different topical intraocular pressure (IOP) lowering molecules have gained an important role in recent years. The use of fixed combinations reduces the number of daily instillations, which promotes adherence to the prescribed medication and diminishes the exposition of the ocular surface to preservatives. The fixed combination of brinzolamide and timolol was recently approved by the European Medicines Agency (EMEA) and is now available in several countries in Europe. It contains two molecules widely used to treat glaucoma: timolol 0.5% (5 mg/ml) and brinzolamide 1% (10 mg/ml) in ophthalmic suspension formulation. This fixed combination is approved for twice-daily instillation to reduce elevated IOP in open-angle glaucoma and ocular hypertension. The brinzolamide/timolol fixed combination provides an approximately 30 – 33% IOP reduction from the untreated baseline IOP of 25 – 27 mmHg; thus, it is more potent than either of its ingredients alone. It is similarly effective but better tolerated than the dorzolamide/timolol fixed combination, which consists of molecules from the same pharmacological classes. The brinzolamide/timolol fixed combination can be used by itself as a separate therapy, but owing to the additivity of its ingredients to IOP-lowering drugs belonging to other classes, it may also be administered adjunctive to other IOP-reducing molecules, most importantly topical prostaglandin analogues. The ocular and systemic tolerance of the brinzolamide/ timolol fixed combination was reported favorable in Phase III studies, but no long-term clinical experience with this preparation is available at present.     

Observational study of patients switched to the fixed travoprost 0.004%/timolol 0.5% combination in Croatia

The purpose of this study was to assess both the benefits of a 3-month travoprost 0.004%/timolol 0.5%fixed combination (trav/tim) regimen in comparison with previous medications for the control of intraocular pressure (IOP) and the tolerability of these drug regimens in glaucoma patients. An observational, non-interventional, open-label study of 406 eyes with primary open angle glaucoma and ocular hypertension was thus undertaken. One drop of trav/tim fixed combination was administered in the evening for 3 months. Patients were divided into five groups according to previous drug regimens: timolol 0.5% monotherapy; betaxolol 0.5% monotherapy; latanoprost 0.005% monotherapy; travoprost 0.004% monotherapy; and dorzolamide 2%/timolol 0.5% fixed combination. Upon medication substitution, the trav/tim fixed combination provided better IOP control and tolerability in all five patient groups. At the 3-month follow up, the mean IOP changes from previous therapy were as follows: 5.2 ± 2.7 mmHg (20.8% change) in timolol 0.5% group; 5.7 ± 2.2 mmHg (22.5% change) in betaxolol 0.5% group; 3.8 ± 2.6 mmHg (24.5% change) in latanoprost 0.005% group; 4.4 ± 2.8 mmHg (20% change) in travoprost 0.004% group; and 3.4 ± 4.1 mmHg (14.5% change) in dorzolamide 2%/timolol 0.5% fixed combination group. The difference between baseline and trav/tim combination patient satisfaction at the 3-month follow-up was significant. Thus, the trav/tim fixed combination provided better IOP control and tolerability than previous mono- or polytherapies.     

Brimonidine

Brimonidine tartrate is a highly selective alpha2-adrenergic receptor agonist indicated for the chronic treatment of glaucoma and ocular hypertension. Glaucoma, a serious worldwide public health problem causing blindness in 5.2 million people, is treated by drugs that lower the intraocular pressure (IOP), a primary risk factor in glaucomatous optic neuropathy. Currently, beta-blockers are the most common therapy. In two 12-month clinical comparison trials with timolol 0.5% (n = 926), twice-daily brimonidine produced IOP lowering comparable to twice-daily timolol. In a 3-month trial with betaxolol 0.25% suspension (n = 206), twice-daily brimonidine was more effective in lowering IOP than twice-daily betaxolol. Brimonidine was well-tolerated ocularly and systemically in these trials. It caused no clinically significant mean changes in heart rate or blood pressure. Brimonidine produced no significant effect on FEV1 in clinical trials, and it is not contraindicated in patients with cardiopulmonary disease. Brimonidine 0.2% dosed twice daily has clinical utility as a first-line drug therapy. It is an effective and safe alternative to beta-blockers, particularly in patients at risk for pulmonary or cardiovascular disease. It decreases aqueous humour production and increases uveoscleral outflow, and has an additive ocular hypotensive effect used concomitantly with other agents. Brimonidine has demonstrated neuroprotective properties in laboratory animal studies. Additional studies are warranted to determine whether brimonidine has clinical benefit in protecting the optic nerve head from glaucomatous damage. Brimonidine is an important contribution to glaucoma management.     

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

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 percentage of IOP reduction compared to dorzolamide 2.0%/timolol maleate 0.5% fixed combination.     

A comparison of the effects of 0.005% latanoprost and fixed combination dorzolamide/timolol on retrobulbar haemodynamics in previously untreated glaucoma patients

OBJECTIVE: To assess the effects of dorzolamide/timolol fixed combination (DTFC) and latanoprost 0.005% on the retrobulbar haemodynamics and intraocular pressure (IOP) of open-angle glaucoma patients. METHODS: 22 consecutive subjects with newly diagnosed, open-angle glaucoma were included in this prospective, examiner masked, randomized, crossover study. The patients were randomized into two different arms. Peak systolic velocity (PSV), end-diastolic velocity (EDV), Pourcelot's resistance index (RI) and intraocular pressure (IOP) were determined at baseline and after 1 month of medical treatment with DTFC or latanoprost 0.005% in both groups. A 4-week washout period, without medical treatment, between study arms was carried out. Primary efficacy variables were the PSV, EDV and RI in the ophthalmic artery (OA) and short posterior ciliary artery (SPCA) and intraocular pressure (IOP). Inter- and intra-group comparisons were performed with a one-way ANOVA test and two-tailed paired Student's t-test respectively. RESULTS: Intraocular pressure (IOP) and colour Doppler imaging (CDI) measurements were similar at baseline. Compared to baseline and washout measurements, only the fixed combination dorzolamide/timolol significantly increased the EDV in the OA and in the SPCA, p = 0.00012 and p = 0.00012, respectively and decreased the resistance index in the ophthalmic and short posterior ciliary arteries, p = 0.00011 and p = 0.00031, respectively. There were no statistically significant differences in the IOP lowering effect of either treatment. CONCLUSION: Over a treatment period of 1 month, only the fixed combination dorzolamide/timolol seems to have a vascular effect on retrobulbar vessels. Further research is necessary to confirm these results.     

Bimatoprost: a pharmacoeconomic review of its use in open-angle glaucoma and ocular hypertension

Bimatoprost (Lumigan) is a prostamide analogue used for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. In comparative clinical trials of up to 1 year in duration, administration of 0.03% bimatoprost ophthalmic solution once daily was more effective than 0.5% timolol twice daily and at least as effective as the prostaglandin analogues 0.005% latanoprost and 0.004% travoprost once daily in terms of reducing IOP and/or achieving target IOP levels. Bimatoprost was also more effective than twice-daily administration of 0.5%/2% timolol/dorzolamide in patients refractory to topical timolol therapy. Although generally well tolerated, bimatoprost is associated with a higher incidence of conjunctival hyperaemia than latanoprost, timolol or the combination of timolol and dorzolamide. Three fully published modelled cost-effectiveness analyses of bimatoprost evaluating cost per treatment success in patients with glaucoma or ocular hypertension have been conducted in the US. The analyses incorporated results of randomised, multicentre clinical trials and used a 1-year time horizon. In the treatment algorithm used in the models, patients not achieving target IOP levels with bimatoprost or comparator required additional medical visits and adjunctive therapy. Bimatoprost was associated with lower costs per treatment success than latanoprost, timolol or timolol/dorzolamide across a range of clinically relevant target IOPs. Results were sensitive to changes in treatment success rates and/or drug acquisition costs. Along with the inherent limitations of economic models, other possible criticisms of the analyses are the use of selected IOP data, and the lack of inclusion of costs associated with conjunctival hyperaemia or other adverse effects of therapy. Various other cost-effectiveness analyses of bimatoprost are available, primarily as abstracts and/or posters. In general, most of these studies have also been favourable for bimatoprost, despite having been conducted in different countries and/or from different perspectives.In conclusion, in patients with open-angle glaucoma or ocular hypertension, bimatoprost is an effective and generally well tolerated therapeutic option, albeit with a relatively high incidence of conjunctival hyperaemia. Although results of modelled cost-effectiveness analyses should be interpreted with due consideration of the limitations of the studies, available pharmacoeconomic data generally support the use of bimatoprost as a cost-effective treatment in this patient population.     

A comparative study on the efficacy, safety, and cost-effectiveness of bimatoprost/timolol and dorzolamide/timolol combinations in glaucoma patients

Aim:

This study was designed to compare the bimatoprost/timolol combination and dorzolamide/timolol combination in glaucoma for efficacy, safety, and cost-effectiveness in a local population of Trichy in the state of Tamilnadu.

Materials and Methods:

Eight-week, randomized, parallel group, open-label study was conducted on 48 patients of open angle glaucoma or ocular hypertension. After initial clinical assessment and baseline investigations, bimatoprost/timolol combination (Group A) was prescribed to 22 patients (2 patients lost after initial assessment) and dorzolamide/timolol combination (Group B) to 24 patients. The patients were reviewed after second and eighth weeks for cure rate and adverse drug reaction monitoring.

Results:

At the end of 8 weeks, the mean reduction in intraocular pressure from baseline was 13.04 mmHg (95% confidence interval (CI): 10.67–14.70) with bimatoprost/timolol combination once daily (P < 0.01) and 9.46 mmHg (95% CI: 7.47–10.5) with dorzolamide/timolol combination twice daily. Both the treatments were safe. Cost-effective range of bimatoprost/timolol combination was lower than that of dorzolamide/timolol combination.

Conclusion:

The fixed combination of bimatoprost/timolol was slightly more effective than that of dorzolamide/timolol combination in reducing IOP, and both treatments were generally well tolerated. Bimatoprost/timolol combination was more cost-effective (cost-effective analysis) than dorzolamide/timolol combination.     

Effect of 2% dorzolamide on retinal blood flow: a study on juvenile primary open-angle glaucoma patients already receiving 0.5% timolol

AIM: To investigate whether dorzolamide modifies peripapillary retinal haemodynamics in juvenile primary open-angle glaucoma (JPOAG) patients treated with timolol. METHODS: In 40 JPOAG subjects, before and after dorzolamide coadministration with timolol, the following examinations were achieved: intraocular pressure (IOP), blood pressure (BP), ocular perfusion pressure (OPP), heart rate (HR), visual field and retinal flowmetry. RESULTS: Adjunctive therapy with dorzolamide induced the following modifications: IOP reduction [1.75 mmHg, 95% confidence interval (CI) 1.23, 2.26; P < 0.05], OPP increase (5.09 mmHg, 95% CI 2.97, 7.20; P < 0.02) and retinal blood flow improvement (35.0 arbitrary units, 95% CI 12.20, 57.80; P < 0.03). BP, HR and visual field indices did not change. CONCLUSIONS: Dorzolamide, in association or in fixed combination with timolol, significantly improves retinal blood flow in JPOAG patients.     

Topical bimatoprost: a review of its use in open-angle glaucoma and ocular hypertension

Bimatoprost, a synthetic prostamide analogue, is a new ocular hypotensive agent indicated for the second-line treatment of open-angle glaucoma and ocular hypertension. The drug is formulated as a 0.03% ophthalmic solution. Bimatoprost lowers intraocular pressure (IOP) by increasing aqueous humour outflow. When applied topically once daily in patients with ocular hypertension or glaucoma, bimatoprost 0.03% significantly reduced IOP. Mean IOP was reduced by approximately 7.5 to 9.2mm Hg 12 hours after drug administration in randomised clinical trials. The reduction in IOP was maintained throughout the 24-hour dosage interval. Once-daily treatment with bimatoprost 0.03% was found to be significantly more effective than timolol 0.5% (administered twice daily as an ophthalmic solution or once daily as a gel-forming solution) in randomised comparative trials in patients with ocular hypertension and glaucoma. Furthermore, after 1 to 6 months' treatment, the percentage of patients reaching a target IOP of < or =17mm Hg was significantly greater in the bimatoprost-treated groups than in those receiving timolol. Bimatoprost 0.03% ophthalmic solution was found to be at least as effective as topical latanoprost 0.005% administered once daily in two clinical trials. Reductions in IOP 16 and 20 hours postdose were greater in patients treated with bimatoprost, indicating superior control of IOP at timepoints throughout the dosage interval. In patients refractory to beta-blocker therapy, treatment with bimatoprost 0.03% produced greater reductions in diurnal IOP measurements than combination therapy with topical dorzolamide 2%/timolol 0.5%; approximately twice as many bimatoprost 0.03% recipients achieved an IOP of < or =16mm Hg. The most commonly reported adverse effect during clinical trials of once-daily bimatoprost 0.03% was conjunctival hyperaemia which occurred in 42 to 46% of patients treated. However, most cases were mild and only 1 to 4% of patients withdrew from treatment as a result. Overall withdrawal rates as a result of adverse events during clinical trials ranged from 2.6 to 7%. Bimatoprost has been reported to cause changes in the pigmentation of the periorbital skin, eyelashes and iris, and increase eyelash growth. The long-term consequences of these effects are unknown. Cardiopulmonary adverse effects, which have been associated with the use of beta-blockers such as timolol, were not reported in clinical trials of bimatoprost. Thus, in clinical trials of up to 1-year duration, bimatoprost 0.03% has been found to be effective in significantly lowering IOP and is generally well tolerated. It provides an alternative treatment option for patients in whom beta-blockers are contraindicated. Furthermore, bimatoprost provides an effective second-line treatment option in patients who do not achieve target IOP with other topical ocular hypotensive agents, or who experience unacceptable adverse effects. Wider clinical use of this drug will establish the place of bimatoprost in the treatment of open-angle glaucoma and ocular hypertension.     

The evolving pharmacotherapeutic profile of brimonidine, an alpha 2-adrenergic agonist, after four years of continuous use

Since its introduction in 1996, use of brimonidine tartrate 0.2% ophthalmic solution (Alphagan, Allergan), a highly selective alpha 2-adrenergic agonist, has become increasingly popular for the initial and long-term management of ocular hypertension and glaucoma. Recently, ongoing clinical comparison trials of up to three years in length have reported sustained intraocular pressure (IOP) lowering efficacy with brimonidine 0.2% b.i.d., which was comparable with timolol 0.5% (Timoptic; Merck & Co.), accompanied by a favourable tolerability and safety profile. Also, many post-market studies have demonstrated the utility of brimonidine 0.2% b.i.d. as mono- and adjunctive therapy. Furthermore, major inroads have been made in the study of other possible pharmacotherapeutic benefits of brimonidine treatment, namely the potential for neuroprotection. This review will present a brief developmental history and examine key pharmacotherapeutic characteristics of brimonidine, including its receptor selectivity, IOP-lowering mechanism of action and potential neuroprotective activities. Moreover, the literature on brimonidine's efficacy and safety profiles in the treatment of ocular hypertension and glaucoma will be perused, and new four-year data from an ongoing double-masked clinical study comparing brimonidine tartrate 0.2% with timolol 0.5%, b.i.d. will be introduced. Brimonidine 0.2% b.i.d. provided sustained IOP-lowering efficacy comparable to timolol 0.5% b.i.d., with no significant differences at trough or peak during year four of continuous use. Visual fields were well preserved in both treatment groups with 93% of brimonidine patients and 91% of timolol patients showing no change or improvement. Brimonidine continued to appear safe and well-tolerated, with no clinically significant effects on mean heart rate or blood pressure, and no serious drug-related adverse events (AEs). Two out of 36 brimonidine patients developed ocular allergy; both were resolved without sequelae. Overall post-market surveillance found no reports of unexpected or serious drug-related AEs. These long-term results, in conjunction with those reported in the literature, suggest that brimonidine 0.2% b.i.d. is a highly appropriate first- and second-line therapy for long-term management of glaucoma and ocular hypertension. Potential neuroprotective effects of brimonidine therapy, which might provide additional vision sparing benefit, although supported by compelling animal studies, await clinical verification.     

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.     

The evolving pharmacotherapeutic profile of brimonidine,an 2-adrenergic agonist,after four years of continuous use

Since its introduction in 1996, use of brimonidine tartrate 0.2% ophthalmic solution (Alphagan^®, Allergan), a highly selective ₂-adrenergic agonist, has become increasingly popular for the initial and long-term management of ocular hypertension and glaucoma. Recently, ongoing clinical comparison trials of up to three years in length have reported sustained intraocular pressure (IOP) lowering efficacy with brimonidine 0.2% b.i.d., which was comparable with timolol 0.5% (Timoptic^®; Merck & Co.), accompanied by a favourable tolerability and safety profile. Also, many post-market studies have demonstrated the utility of brimonidine 0.2% b.i.d. as mono- and adjunctive therapy. Furthermore, major inroads have been made in the study of other possible pharmacotherapeutic benefits of brimonidine treatment, namely the potential for neuroprotection. This review will present a brief developmental history and examine key pharmacotherapeutic characteristics of brimonidine, including its receptor selectivity, IOP-lowering mechanism of action and potential neuroprotective activities. Moreover, the literature on brimonidine’s efficacy and safety profiles in the treatment of ocular hypertension and glaucoma will be perused, and new four-year data from an ongoing double-masked clinical study comparing brimonidine tartrate 0.2% with timolol 0.5%, b.i.d will be introduced. Brimonidine 0.2% b.i.d. provided sustained IOP-lowering efficacy comparable to timolol 0.5% b.i.d., with no significant differences at trough or peak during year four of continuous use. Visual fields were well preserved in both treatment groups with 93% of brimonidine patients and 91% of timolol patients showing no change or improvement. Brimonidine continued to appear safe and well-tolerated, with no clinically significant effects on mean heart rate or blood pressure, and no serious drug-related adverse events (AEs). Two out of 36 brimonidine patients developed ocular allergy; both were resolved without sequelae. Overall post-market surveillance found no reports of unexpected or serious drug-related AEs. These long-term results, in conjunction with those reported in the literature, suggest that brimonidine 0.2% b.i.d. is a highly appropriate first- and second-line therapy for long-term management of glaucoma and ocular hypertension. Potential neuroprotective effects of brimonidine therapy, which might provide additional vision sparing benefit, although supported by compelling animal studies, await clinical verification.     

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.     

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.