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.     

Topical brimonidine 0.2%/timolol 0.5% ophthalmic solution: in glaucoma and ocular hypertension

A fixed combination of brimonidine (a highly selective alpha(2)-adrenergic agonist) and timolol (a non-selective beta-blocker) [brimonidine 0.2%/timolol 0.5% ophthalmic solution; brimonidine/timolol] is available for the topical treatment of glaucoma and ocular hypertension (OH). Brimonidine and timolol decrease elevated intraocular pressure (IOP) by complementary mechanisms of action and have an additive effect when coadministered to healthy volunteers and patients with glaucoma or OH. When assessed over a 3- or 12-month period in large, well designed clinical studies, brimonidine/timolol instilled twice daily (one drop in each eye) was superior to monotherapy with the individual components instilled two (brimonidine) or three (timolol) times daily, and noninferior to concomitant therapy with the individual components instilled twice daily, in lowering raised IOP in patients with glaucoma or OH. In small, randomised, comparative studies of 1 or 3 months' duration, the IOP-lowering effect of brimonidine/timolol twice daily was similar or superior to that of fixed combination dorzolamide 2%/timolol 0.5% ophthalmic solution (dorzolamide/timolol) twice daily (preliminary data). Brimonidine/timolol is generally well tolerated with a predictable local and systemic adverse event profile based on that of the individual components used alone and concomitantly. No unexpected or serious adverse events associated with the fixed combination were reported in key clinical trials. Brimonidine/timolol may be advantageous over dorzolamide/timolol with respect to ocular tolerability and comfort (preliminary data).     

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.     

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.     

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.     

Bimatoprost: a member of a new class of agents,the prostamides,for glaucoma management

Bimatoprost, a synthetic analogue of endogenous prostamides, is in development as a topical ocular hypotensive agent for the treatment of glaucoma and ocular hypertension. Prostamides are a newly discovered class of compounds that have been shown to have potent ocular hypotensive activity in the laboratory. Bimatoprost mimics the endogenous prostamides by lowering intraocular pressure (IOP). Bimatoprost provides outstanding control of IOP throughout the day, and a high percentage of patients receiving bimatoprost achieve the low target pressures important for clinical success. In controlled clinical trials, bimatoprost 0.03% given once daily has displayed efficacy superior to timolol 0.5% given twice daily, the current standard for therapy. Analysis of pooled six month data from two large Phase III trials demonstrated that mean IOP was consistently 2 - 3 mmHg lower with bimatoprost q.d. than with timolol b.i.d. Bimatoprost 0.03% q.d. has also been shown to provide significantly better diurnal IOP control than latanoprost 0.005% q.d., probably the most efficacious topical medication currently available. Patients receiving bimatoprost q.d. were more likely than timolol or latanoprost patients to achieve low target pressures. In all clinical evaluations, bimatoprost q.d. has been demonstrated to be safe and well-tolerated. Bimatoprost will likely be available for clinical use in 2001 and it has great potential to be superior to all other medications in IOP-lowering efficacy. It is anticipated that bimatoprost will have an important role in therapy for glaucoma and ocular hypertension.     

Bimatoprost: a member of a new class of agents, the prostamides, for glaucoma management

Bimatoprost, a synthetic analogue of endogenous prostamides, is in development as a topical ocular hypotensive agent for the treatment of glaucoma and ocular hypertension. Prostamides are a newly discovered class of compounds that have been shown to have potent ocular hypotensive activity in the laboratory. Bimatoprost mimics the endogenous prostamides by lowering intraocular pressure (IOP). Bimatoprost provides outstanding control of IOP throughout the day, and a high percentage of patients receiving bimatoprost achieve the low target pressures important for clinical success. In controlled clinical trials, bimatoprost 0.03% given once daily has displayed efficacy superior to timolol 0.5% given twice daily, the current standard for therapy. Analysis of pooled six month data from two large Phase III trials demonstrated that mean IOP was consistently 2 - 3 mmHg lower with bimatoprost q.d. than with timolol b.i.d. Bimatoprost 0.03% q.d. has also been shown to provide significantly better diurnal IOP control than latanoprost 0.005% q.d., probably the most efficacious topical medication currently available. Patients receiving bimatoprost q.d. were more likely than timolol or latanoprost patients to achieve low target pressures. In all clinical evaluations, bimatoprost q.d. has been demonstrated to be safe and well-tolerated. Bimatoprost will likely be available for clinical use in 2001 and it has great potential to be superior to all other medications in IOP-lowering efficacy. It is anticipated that bimatoprost will have an important role in therapy for glaucoma and ocular hypertension.     

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.     

Distribution of brimonidine into anterior and posterior tissues of monkey, rabbit, and rat eyes.

The objectives of the study were to evaluate the distribution of brimonidine (alpha2-adrenergic agonist) into anterior and posterior ocular tissues. Single or multiple doses of a 0.2 or 0.5% brimonidine tartrate solution were administered to one or both eyes of monkeys or to one eye of rabbits. Brimonidine was administered intraperitoneally to rats. After topical administration, [14C]brimonidine was rapidly absorbed into the cornea and conjunctiva and distributed throughout the eye. [14C]Radioactivity was higher and cleared more slowly in pigmented tissues (iris/ciliary body, choroid/retina, and optic nerve) than in nonpigmented tissues. Single and multiple dosing led to a similar drug distribution, with higher levels of brimonidine measured in pigmented tissues after multiple dosing. Most of the radioactivity extracted from ocular tissues represented unchanged brimonidine. In the rabbits and the monkey treated in only one eye, levels of radioactivity in the untreated eye were low, consistent with the low systemic levels and rapid drug clearance. Posterior ocular tissue concentrations of radioactivity exceeded systemic blood concentrations. The vitreous humor brimonidine concentrations in monkeys treated topically with 0.2% brimonidine tartrate was 82 +/- 45 nM. Vitreous levels in rabbits confirmed the penetration of brimonidine to the posterior segment. Similar concentrations of brimonidine (22 to 390 nM) were measured in the vitreous and retina of rats injected intraperitoneally with brimonidine. Both topically applied and systemically administered brimonidine reach the back of the eye at nanomolar concentrations sufficient to activate alpha2-adrenergic receptors. The brimonidine levels achieved at the retina are relevant for neuroprotection models.     

Efficacy,safety, and current applications of brimonidine

Background: The use of brimonidine to lower intraocular pressure has been the subject of considerable investigation. Variations of the initially approved drug including agents of a lower concentration (Alphagan^® P 0.15 and 0.1%, Allergan, Inc., Irvine, CA, USA) and a fixed-combination mating brimonidine with timolol (Combigan^®, Allergan) evolved the marketing and application of this therapy. Objective: We review available evidence regarding the efficacy and side effect profile of brimonidine as well as its role in glaucoma management. Results/conclusion: Brimonidine is an important component of topical glaucoma treatment that is most limited by local ocular intolerance.     

Fixed-combination brimonidine–timolol versus latanoprost in glaucoma and ocular hypertension: a 12-week,randomized, comparison study

Abstract

Objective:

To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of fixed-combination brimonidine 0.2%–timolol 0.5% compared with latanoprost 0.005% in patients with glaucoma or ocular hypertension.     

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.     

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.     

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。     

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.     

Pupillometry study of brimonidine tartrate 0.2% and apraclonidine 0.5%

This study investigated possible effects of brimonidine tartrate 0.2% and apraclonidine 0.5% on pupil diameter. Ten subjects between 20 and 40 years of age participated. A Colvard pupillometer (Oasis Medical) was used to measure pupil diameter. Baseline and serial measurements were obtained at 3 luminance levels (>6.4, <0.82-0.4, and <0.2-0.02 cd/m(2)) during a 4-hour interval following instillation of 1 drop of brimonidine tartrate 0.2% or apraclonidine 0.5% in one eye versus a placebo in the contralateral eye. The measurements for each drug were obtained on different days. A nested random effects model controlling for subject's age, race, and sex was used for statistical analysis. A maximum reduction in pupil diameter was observed at 90 minutes from instillation (1.40 mm at >6.4 cd/m(2), 1.69 mm at <0.82-0.4 cd/m(2), and 1.55 mm at <0.2-0.02 cd/m(2)) for brimonidine tartrate 0.2%. At all time intervals and illumination levels, miosis (P < .01) occurred. Apraclonidine 0.5% did not produce a significant effect on pupil diameter. Brimonidine tartrate 0.2% produced a moderate miotic effect. No effect was observed for apraclonidine 0.5%. A predominant agonistic effect on α-2 receptors of the iris dilator may explain this behavior.     

科比根治疗开角型青光眼和高眼压症的疗效及安全性

目的：研究科比根治疗开角型青光眼和高眼压症的疗效及安全性。方法采用对照研究手段,将符合条件的患者随机分组进行科比根?（溴莫尼定和噻吗洛尔固定复合滴眼液）和非固定联合制剂治疗（0．2％酒石酸溴莫尼定滴眼液及0．5％噻吗洛尔滴眼液）比较。结果在5周的对比治疗后,分析疗效、治疗安全性,科比根?治疗效果与非固定联合制剂治疗效果接近,未出现新的与治疗有关不良事件,未观察到其他治疗安全性的明显差异。结论科比根治疗开角型青光眼和高眼压症的方法与非固定联合制剂的疗效和安全性相似。     

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.     

Ocular levobunolol. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy

Levobunolol is a potent non-selective beta-adrenoceptor blocking agent used for the topical treatment of increased intraocular pressure in patients with chronic open angle glaucoma or ocular hypertension. In comparative studies of up to 2 years' duration levobunolol 0.5 to 1% reduced intraocular pressures by about 30% and adequately controlled intraocular hypertension in 50 to 85% of those treated. These results were significantly superior to those produced by placebo and comparable to the responses achieved with ocular timolol in double-blind controlled trials. Levobunolol has been well tolerated, producing only minor changes in objective and subjective ophthalmic and systemic parameters. Adverse reactions resulted in approximately 5% of patients withdrawing from treatment with levobunolol which was equivalent to that observed with timolol. Thus, ocular levobunolol is a well-tolerated and effective therapy for the management of raised intraocular pressure, and is a suitable alternative to ocular timolol in patients with chronic open angle glaucoma or ocular hypertension.     

Brimonidine tartrate for the treatment of glaucoma

Introduction: Brimonidine tartrate is a commonly used eyedrop for short- and long-term lowering of intraocular pressure. Its use has been popularized due to its effects on aqueous suppression and uveoscleral outflow, as well as the suggestion of neuroprotection. Although available with alternative preservative vehicles, brimonidine is associated with high rates of local allergy and is contraindicated in breastfeeding women, neonates, young children, and the elderly due to risk of central nervous system depression. Other topical agents with differing advantages have challenged brimonidine’s role in the treatment algorithm of ocular hypertension and glaucoma.

Areas covered: The authors review the development of topical alpha-adrenergic agonists, with particular attention to the currently available formulations of brimonidine tartrate. Its mechanism of action, pharmacodynamics and safety, and clinical efficacy are analyzed.

Expert opinion: Despite clinical familiarity with brimonidine after two decades of use, agents that offer daily dosing, nocturnal effect, and more favorable ocular and systemic side effect profiles have ultimately led to brimonidine’s adjunctive use in patients with elevated intraocular pressure or high- or low-tension glaucomas. Still, brimonidine may be advantageous in patients undergoing laser trabeculoplasty or iridotomy, in certain forms of glaucoma, or in pregnant individuals prior to the last trimester, underscoring its clinical importance.