Preservative-free versus preserved brimonidine %0.15 preparations in the treatment of glaucoma and ocular hypertension: short term evaluation of efficacy,safety, and potential advantages

Abstract

Purpose: To compare the efficacy, safety, and potential advantages of the preservative-free versus preserved brimonidine %0.15 preparations in patients with primer open-angle glaucoma (POAG) or ocular hypertension (OHT).

Methods: Forty-two eyes of the 21 treatment-naive patients with POAG or OHT were enrolled in this study. Eyes were randomly assigned to receive brimonidine-purite 0.15% or preservative-free brimonidine 0.15% two times daily. Efficacy of the two eye drops was assessed by measuring the intraocular pressure (IOP) at 9–10 am at baseline and week 4. Safety and potential advantages of the drops were evaluated at weeks 4 in terms of ocular symptoms and tear parameters. Ocular symptom values of the patients were evaluated with a scale of 0–4 (0?=?no discomfort and 4?=?severe discomfort).

Results: Both of the brimonidine tartrate formulations resulted in statistically similar IOP reduction (preserved formulation; ?5.2?mmHg [22.9% reduction] preservative-free formulation; ?5.7?mmHg [24.1% reduction], p?=?0.37). It was found that brimonidine tartrate formulations with and without topical preservatives did not produce a statistically significant difference in pain, stinging, and blurred vision at the upon instillation (p?>?0.05). However, the burning sensation was significantly higher in the preservative-free formulation at the first instillation compared to the preserved formulation (p?=?0.01). Also, there was no statistically significant difference between the two formulations in terms of symptoms (itching, burning, tearing, stinging, and photophobia) and tear parameters during the day (p?>?0.05).

Conclusions: Although topical preservative-free brimonidine tartrate treated eyes had a more burning sensation at the first drop, the two formulations were similar in terms of ocular tolerability in the short term period. Also, both formulations were found to reduce IOP at a similar rate.     

An evaluation of the fixed-combination of latanoprost and timolol for use in open-angle glaucoma and ocular hypertension

Glaucoma is one of the leading causes of irreversible blindness worldwide. Although there is no cure for this chronic disease, medical treatment is aimed at reducing levels of intraocular pressure (IOP) using ocular hypotensive agents. Very often, patients require more than one IOP-reducing drug, resulting in complex medication regimens that may be difficult to maintain and that can lead to non-compliance. A fixed-combination (FC) ophthalmic solution consisting of the prostaglandin, latanoprost (0.005%), and the β-blocker, timolol (0.5%), is now available. The primary mechanism of action of latanoprost is to increase uveoscleral outflow whereas timolol lowers IOP levels by decreasing the formation of aqueous humor in the ciliary epithelium. Due to the unique mechanism of action of latanoprost, once-daily dosing of one drop of FC latanoprost/timolol results in additional IOP reduction compared with either drug administered separately. FC latanoprost/timolol is well-tolerated and has a safety profile similar to that of its individual components. This combination drug provides a safe, effective and convenient alternative for the treatment of patients with elevated IOP levels uncontrolled with monotherapy.     

汉防己碱滴眼液对慢性高眼压兔模型治疗作用的研究

【】目的：探讨汉防己碱滴眼液对慢性高眼压兔模型的治疗作用。方法：新西兰兔18只,随机分为空白组(6只)、模型组(6只)及给药组(6只),利用复方卡波姆溶液进行慢性高眼压造模,给药组家兔给予汉防己碱滴眼液(浓度0.1 mg/ml)滴眼,模型组及空白组则给予等量生理盐水滴眼。治疗7天后处死各组家兔,取视网膜,分为两份,并分别用Thy-1染色及制备匀浆。利用光镜观测Thy-1染色并对其RGCs进行计数;检测匀浆液中SOD,GSH-PX及MDA含量。结果：空白组,给药组与模型组RGCs计数分别为(21.2±1.7),(20.1±2.5)及(15.2±2.3)个/高倍视野,空白组与给药组分别与模型组相比较,差异均具有统计学意义(P＜0.05);模型组中内丛状层变薄,外核层细胞排列紊乱、数目减少且间隙扩大;给药组及空白组家兔视网膜各层组织层次分明、结构清晰且细胞排列整齐。给药组及空白组家兔视网膜匀浆液中SOD,MDA及GSH-PX水平均明显优于模型组。结论：汉防己碱滴眼液对慢性高眼压兔模型具有较好的治疗作用,值得开展深入研究。     

Efficacy and safety of tafluprost 0.0015% and timolol maleate 0.5% fixed combination in patients with ocular hypertension or open-angle glaucoma

Introduction: Lowering intraocular pressure (IOP) is at present the only therapeutic approach to the treatment of glaucoma proven to be successful. The choice of therapy must take into account efficacy, tolerability, safety, quality of life, adherence and cost. Monotherapy fails to achieve a satisfactory IOP reduction in 40 – 75% of glaucoma patients after > 2 years of therapy. So far, three prostaglandin/timolol maleate 0.5% fixed combinations (FCs) are available.

Areas covered: This review provides a background on the tafluprost–timolol FC (TTFC, Santen Oy) and its individual compounds. It summarizes the data on efficacy and safety, including comparative data with prostaglandin/timolol FCs already available.

Expert opinion: Tafluprost is a preservative-free prostaglandin analog with a similar IOP efficacy when compared with other prostaglandin analogs. However, its improved adverse effect profile seems to be beneficial in patients sensitive to preservatives. The preservative-free TTFC has no market authorization yet. Only one Phase III trial was published so far, but results are promising in terms of efficacy, tolerability and safety. It is likely that the TTFC will play a role in the treatment of open-angle glaucoma and ocular hypertension.     

他氟前列素治疗开角型青光眼和高眼压症的有效性及安全性评价

目的:综述他氟前列素滴眼液降低开角型青光眼和高眼压症患者眼内压的有效性及安全性评价。方法:使用"他氟前列素"、"开角型青光眼"、"高眼压症"、"有效性"、"安全性"作为检索词在PubMed数据库和中文数据库维普全文、电子期刊等对已发表的文献进行检索,检索2004年至2015年英文文献共52篇及中文文献多篇,包括多中心临床研究及药品信息资料,并对检索结果进行归纳性分析。结果:现有的研究已显示,他氟前列素是一种有效降低眼内压的药物。循证医学也发现他氟前列素安全有效,患者依从性良好。不含防腐剂他氟前列素的降眼压效果与含防腐剂的相同。结论:研究提示,他氟前列素每日1次滴眼可安全有效地降低开角型青光眼及高眼压症患者的眼内压。     

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.     

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.     

持续高眼压状态下手术治疗急性闭角型青光眼33例

目的探讨对降眼压治疗效果不佳的闭角型青光眼在高眼压状态下行手术治疗的疗效。方法回顾性分析笔者所在医院2007年5月～2010年10月治疗的33例33眼应用药物不能控制眼压的急性闭角型青光眼患者,所有患者均行复合式小梁切除术治疗。术后随访6～12个月。结果所有患者手术均顺利完成,术中术后均未出现严重并发症,术后视力获得明显的提高;术后1周所有患者眼压均在8～11mmHg,经6～12个月随访,患者眼压基本控制在14.36～21.58mmHg。结论原发性闭角型青光眼持续高眼压状态下的复合式小梁切除术是安全有效的。手术治疗的术前、术中、术后都应积极处理高眼压,提高手术的成功率,预防和减少术中及术后并发症的发生。     

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。     

Evaluation of eye drop administration technique in patients with glaucoma or ocular hypertension

Abstract

Objective:

To evaluate eye drop administration by patients at multiple visits in the setting of a randomized controlled trial.     

Preservative-free tafluprost/timolol fixed combination: comparative 24-h efficacy administered morning or evening in open-angle glaucoma patients

ABSTRACT

Background

Ideal dosing for the preservative-free (PF) tafluprost/timolol fixed combination (TTFC) remains to be elucidated.     

Latanoprostene bunod ophthalmic solution 0.024% for IOP lowering in glaucoma and ocular hypertension

Introduction: Intraocular pressure (IOP)-lowering has been demonstrated to slow the progression or onset of visual field loss in open-angle glaucoma (OAG) or ocular hypertension (OHT). Pharmacological lowering of IOP is the most common initial intervention in patients with OAG or OHT, however, many patients will require more than one therapy to achieve target IOP. Latanoprostene bunod is a novel nitric oxide (NO)-donating prostaglandin F2α analog for the reduction of IOP.

Areas covered: Current knowledge concerning the mechanism of action of latanoprostene bunod is presented. Additionally, clinical safety and efficacy data from published Phase 1 (KRONUS), Phase 2 (VOYAGER, CONSTELLATION) and Phase 3 (APOLLO, LUNAR, JUPITER) studies are reviewed.

Expert opinion: Latanoprostene bunod is a dual mechanism, dual pathway molecule, consisting of latanoprost acid, which is known to enhance uveoscleral (unconventional) outflow by upregulating matrix metalloproteinase expression and remodeling of the ciliary muscle’s extracellular matrix, linked to an NO-donating moiety, which enhances trabecular meshwork/Schlemm’s canal (conventional) outflow by inducing cytoskeletal relaxation via the soluble guanylyl cyclase-cyclic guanosine monophosphate (sGC-cGMP) signaling pathway. Latanoprostene bunod 0.024% solution applied topically once daily appears more effective in reducing IOP in OHT and OAG subjects than either latanoprost or timolol, with a side effect profile similar to that of latanoprost.     

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.     

毛果芸香碱联合拉坦前列素治疗原发性急性闭角型青光眼的疗效观察

目的探讨毛果芸香碱联合拉坦前列素治疗原发性急性闭角型青光眼的疗效及安全性。方法随机选取2014年5月—2015年1月海南医学院附属医院眼科收治的原发性急性闭角型青光眼患者92例,随机分为对照组和治疗组,每组各46例。对照组给予拉坦前列素滴眼液,1滴/次,1次/d。治疗组在对照组的基础上给药5 min后滴加硝酸毛果芸香碱滴眼液,2~3滴/次,2~4次/d。两组均连续治疗6个月。观察两组的临床疗效,同时比较两组患者治疗前后的视力、瞳孔直径、眼压、血流动力学指标舒张末期血流速度(EDV)、收缩期峰值血流速度(PSV)、血管阻力指数(RI)及不良反应。结果治疗后,对照组和治疗组的总有效率分别为82.61%、95.65%,两组比较差异有统计学意义(P0.05)。治疗1、3、6个月,两组患者的患眼视力、瞳孔直径均较同组治疗前显著改善,同组治疗前后差异具有统计学意义(P0.05);且治疗后,治疗组患者的视力、瞳孔直径改善程度明显优于同期对照组,两组比较差异具有统计学意义(P0.05)。对照组治疗3、6个月,治疗组治疗1、3、6个月的眼压与同组治疗前相比均有显著下降,且治疗组患者眼压下降情况明显优于同期对照组(P0.05);治疗1、3、6个月,治疗组患者的EDV、PSV均明显高于对照组,而RI则明显低于对照组,同组治疗前后差异有统计学意义(P0.05);且治疗组的改善程度优于对照组,两组比较差异有统计学意义(P0.05)。对照组和治疗组的不良反应发生率分别为10.87%、0.00%,两组比较差异有统计学意义(P0.05)。结论毛果芸香碱联合拉坦前列素治疗原发性急性闭角型青光眼疗效显著,可明显改善视力,有效提高视野,降低眼压,安全性高,具有一定的临床推广应用价值。     

Corneal damage and its recovery after instillation of preservative-free versus preserved latanoprost eye drops

Abstract

Purpose: Latanoprost ophthalmic solution is highly effective as a therapeutic agent for glaucoma and is applied worldwide. However, harmful effects on the corneal surface have been reported regarding the commercially available latanoprost ophthalmic solution. Corneal surface toxicity may be caused by the added preservative of the ophthalmic solution. In order to ascertain whether latanoprost itself can damage the cornea or if this is solely due to the added preservatives, this study attempted to determine the corneal changes that occur at different time periods following usage of preservative-free versus preserved latanoprost eye drops.

Materials and methods: Preservative-free latanoprost eye drops (Monoprost^®) or preserved latanoprost eye drops (Xalatan^®) containing 0.02% benzalkonium chloride (BAC) were instilled in the corneas of rabbits. For each of the two different eye drop solutions, the rabbits used in this experiment were divided into three exposure groups: 1?minute, 24?hour, and 1?week groups. Corneal transepithelial electrical resistance (TER) and scanning electron microscopy (SEM) were examined immediately (1?minute) after instillation, at 24?hours after instillation, and at 24?hours after 1?week of daily instillations of latanoprost. Hank’s balanced salt solution was used in the control group.

Results: The mean corneal TER of the control group was 933.8?±?279.0 Ω cm². In preservative-free latanoprost instilled corneas, there was no significant decrease in the TER or morphological changes at any of the time points, with the relative TER values of 117?±?38%, 100?±?34%, and 93?±?21% for 1?minute, 1?day, and 1?week time points, respectively. In preserved latanoprost instilled corneas, SEM showed that only the immediate group exhibited superficial cell damage and a significant decrease in the corneal TER compared to the controls and other time points and to the immediate preservative-free latanoprost corneas. In the preserved latanoprost groups, the relative TER values were 18?±?5%, 110?±?28%, and 92?±?10%, for the three respective observation time points.

Conclusions: Preservative-free latanoprost can be safely instilled to the corneal epithelium. Latanoprost with 0.02% BAC has an immediate deleterious impact on the corneal epithelium; however, it disappears within 24?hours after instillation.     

A preliminary risk-benefit assessment of latanoprost and unoprostone in open-angle glaucoma and ocular hypertension.

Latanoprost and unoprostone (isopropyl unoprostone) represent the first commercially available prostaglandin analogues to be used for the treatment of glaucoma. Both compounds reduce intraocular pressure by enhancing uveoscleral outflow. Latanoprost, when used once daily in the evening, produces a greater reduction in pressure than timolol. Latanoprost produces mild conjunctival hyperaemia compared with timolol in some patients. Darkening of the irides has been reported, especially in green-brown, yellow-brown and blue/grey-brown irides. Hypertrichosis and hyperpigmentation of the eyelashes have also been demonstrated. Although latanoprost has not been proven to cause uveitis or cystoid macular oedema, case reports of an association exist. Latanoprost does not produce systemic adverse effects nor does it alter routine blood analyses. Unoprostone, when given twice daily, produces less of a reduction in intraocular pressure than timolol or latanoprost. Three times daily use may be required to approach the effectiveness of timolol. Unoprostone may have a similar adverse effect profile to latanoprost, but may to cause more corneal epithelial problems. Unoprostone is also not known to cause systemic adverse effects. Both agents are welcome additions to the treatment of glaucoma. However, additional studies and more experience are needed with each agents.     

Investigational and experimental drugs for intraocular pressure reduction in ocular hypertension and glaucoma

Introduction: Intraocular pressure (IOP) is the most significant modifiable risk factor to prevent onset or progression of glaucoma. Glaucoma prevalence continues to increase, emphasizing the need for improved ocular hypotensive treatment options. To try to improve on both tolerance and IOP control of currently available therapies, different receptors or mechanisms are being explored to reduce IOP more effectively and to improve tolerance.

Areas covered: We review synthetic topical and oral drugs in early development for the management of ocular hypertension and glaucoma.

Expert opinion: New therapeutic agents for IOP control have been discovered; some appear to be reasonably tolerated. IOP reduction may be limited with some agents, but other benefits although unproven may compensate for this, such as less ocular surface disease, enhanced neuro-protection or increased ocular blood flow. Further product development promises improved treatment options for ocular hypertensives and glaucoma sufferers.     

拉坦前列素滴眼液治疗青光眼

目的 :观察用降眼压药物而眼压不能控制的病人 ,加用拉坦前列素滴眼液治疗的临床疗效。方法 :2 4例病人 (共 2 4只病眼 ) ,男性 10例 ,女性 14例 ,年龄 (5 0±s12 )a ,共 2 4只病眼用 2种以上降眼压药物而眼压不能控制 ,加用 0 .0 0 5 %拉坦前列素滴眼液滴病眼 ,每晚 1次 ,疗程至少 3mo。结果 :用2种降眼压药有 9例 (38% ) ,用 3种以上降眼压药15例 (6 2 % ) ,其中有 8例 (33% )需口服乙酰唑胺片降眼压。 2 4例病人加用 0 .0 0 5 %拉坦前列素滴眼液 1wk ,1mo和 3mo后 ,眼压由 (3.6 4± 0 .18)kPa降至 (2 .19± 0 .11)kPa ,(2 .18± 0 .11)kPa ,(2 .14 0± 0 .0 10 )kPa ,均P <0 .0 1。眼压降至正常 15例 (6 2 % ) ,眼压降低但未至正常 7例 (2 9% ) ,无效为 2例 (8% )。结论 :对用降眼压药物而眼压不能控制的病人 ,加用拉坦前列素滴眼液可以有效的控制眼压 ,防止青光眼对视功能的进一步损伤     

拉坦前列素和溴莫尼定对青光眼视神经血供影响的对比研究

目的观察拉坦前列素和溴莫尼定连续应用12周对眼血流的影响。方法选择原发性开角型青光眼患者69例,随机分成2组,分别滴用0.005%拉坦前列素每日1次和0.2%溴莫尼定每日2次,疗程均为12周。应用彩色超声多普勒成像系统测量视网膜中央动脉和睫状后短动脉的血流动力学参数变化。结果拉坦前列素组视网膜中内动脉(CRA)和睫状后短动脉(PCA)的各项血流动力学指标与治疗前相比差异有统计学意义(P<0.05),血流的收缩期峰值血流速度(PSA)和舒张末期血流速度(EDV)较治疗前均增加,阻力系数(RI)较治疗前降低。而溴莫尼定组CRA和PCA的各项血流动力学指标与治疗前相比差异无统计学意义(P>0.05)。治疗12周后拉坦前列素组PCA的PSV及EDV均高于溴莫尼定组,RI则低于溴莫尼定组,且差异有统计学意义(P<0.050;2组的CRA血流参数,拉坦前列素组的PSV明显高于溴莫尼定组(P<0.05),而EDV及RI差异无统计学意义(P>0.05)。结论拉坦前列素在改善原发性开角型青光眼患者眼血流方面优于溴莫尼定。