抗青光眼新药brimonidine的研究及应用进展

α2 肾上腺素能受体促效剂brimonidine(BMN) ,是一种较新型的降眼压药物。近年来的研究结果表明 ,BMN对α2 受体有高度选择性 ,降眼压效果确实而持久 ,全身和局部副作用小 ,不引起视神经的缺血性病变 ,具有神经保护作用。是一类安全有效的抗青光眼药物 ,尤其适用于对 β 阻滞剂禁忌的患者。

Brimonidine──青光眼药物的最新进展

Brimonidne是一种新型高度选择性的a2－肾上腺素能受体激动剂，对a2－受体的选择性比可乐定高7～12倍，比阿普拉可乐定高23～32倍。对动物实验、正常志愿者、原发性开角型青光眼和高眼压症者、氢激光术后眼压升高者均有显著的降眼压作用。此药可以长期应用，每日2次。常用浓度为0．2％，对氩激光术后者可用0．5％浓度。对瞳孔大小、心律和血压无明显影响。副作用极少发生，而且具有神经保护作用。其降眼压作用机制为减少房水生成并增加房水的巩膜色素膜外流。与0．5％的座吗心安和0．25％的Betaxolol（商品名：贝特舒）相比，其降眼压作用大于后两者，而且全身和局部副作用较少。因此，Brimonidine是一种大有前途的药，可以成为青光眼的首选治疗药物。

0.2%brimonidine对开角型青光眼及高眼压症的临床疗效

目的 :评价 0 .2 %brimonidine滴眼对原发性开角型青光眼及高眼压症的降眼压效果及安全性。方法 :2 5例患者 4 1只眼纳入为期 6个月的前瞻性研究。在停用其他抗青光眼药物足够长的时间后测量基础值 ,予 0 .2 %bri monidine点眼每日两次 (8AM ,8PM) ,每月复查一次 ,测量低谷眼压 (用药 12h后眼压 )和高峰眼压 (用药 2h后眼压 )等 ,每 3个月复查视野一次。结果 :每次随访中 0 .2 %brimonidine均能显著降低患者低谷及高峰眼压 (P <0 .0 5 ) ;复查2 4h眼压波动每一时间眼压均较用药前显著降低 (P <0 .0 5 ) ;用药后 3月及 6月复查视野示药物对视功能无明显影响 (P >0 .0 5 )。观察期间未发现严重全身副作用。结论 :0 .2 %brimonidine对开角型青光眼及高眼压症具有稳定的降眼压效果 ,是一种具有良好耐受性 ,同时安全。

Brimonidine对青光眼治疗作用的研究

近几年来，美、欧眼科学者就Ｂｒｉｍｏｎｉｄｉｎｅ（ＢＭＮ）对青光眼的治疗作用进行了广泛研究，结果表明ＢＭＮ对青光眼患者有明显降眼压作用。其降眼压作用与噻吗心安相似，强于倍他心安，但确无噻吗心安所致的心肺副作用。此外，该药对视神经还具有保护作用。ＢＭＮ可引起部分患者出现眼过敏反应，但其发生率比氨可乐定少得多。总之，ＢＭＮ安全、有效，可作为治疗青光眼的一线用药，尤其适用于对β受体阻断剂有绝对或相对禁忌证的患者。

Effect of brimonidine tartrate on basophil activation in glaucoma patients

AIM:To evaluate the mechanism of which brimonidine tartrate 0.15%causes clinical hypersensitivity.METHODS:A prospective case-control study comparing 8 glaucoma patients with clinical hypersensitivity to brimonidine to a control group consisting 13 healthy volunteers.Blood samples were stimulated with brimonidine 0.15%,timolol 0.5%or brimonidine tartrate/timolol maleate 0.2%/0.5%.Premixed antibodies(CD63/FITC and aIgE/PE)were added for direct staining and whole-blood samples were lysed,fixed and analyzed by a flow cytometer.The basophil population was defined by high IgE cell expression.Degranulation was identified by the expression of the activation molecule CD63.RESULTS:Basophil activation was not significant when comparing percent of activated basophils of patients and healthy controls after exposure to brimonidine(2.58%,2.45%,respectively,P=0.72).There was a significant suppression of basophil activation when a combination of brimonidine-timolol(0.87%)was compared to timolol(2.27%;P=0.012)and to brimonidine alone(2.58%;P=0.017).CONCLUSION:The results of our study do not support the hypothesis that brimonidine induces an immediate allergic reaction.Basophil activation was suppressed by the presence ofβ-blockers in patients hypersensitive to brimonidine and in healthy individuals.This finding indicates that timolol suppress brimonidine drug reaction by a different mechanism.

Comparison of brimonidine-timolol and dorzolamidetimolol in the management of intraocular pressure increase after phacoemulsification

AIM: To compare the effectiveness of brimonidine/timolol fixed combination(BTFC) and dorzolamide/timolol fixed combination(DTFC) in the management of short-term intraocular pressure(IOP) increase after phacoemulsification surgery.·METHODS: Eighty eyes of 80 patients undergoing phacoemulsification and intraocular lens(IOL)implantation were randomly assigned into three groups.Group 1 consisted of 28 eyes and represented the control group. Group 2 consisted of 25 eyes undergoing phacoemulsification surgery and BTFC was instilled at the end of surgery. Group 3 consisted of 27 eyes undergoing phacoemulsification surgery and DTFC was instilled at the end of surgery. IOP was measured preoperatively and 6, 24 h and 1wk postoperatively.·RESULTS: There was no statistically significant difference in preoperative baseline IOP among the three groups(P =0.84). However, IOP was significantly lower in groups 2 and 3 compared to the control group(P <0.05 for all comparisons) at all postoperative visits. There was no significant difference between groups 2 and 3 at any visit. Eight eyes(28.6%) in the control group, two(8%) in Group 2 and one(3.7%) in Group 3 had IOP >25 mm Hg at 6h after surgery(P =0.008). However, IOP decreased and was >25 mm Hg in only one eye in each group at24 h after surgery.·CONCLUSION: BTFC and DTFC have similar effects in reducing increases in IOP after phacoemulsificationsurgery and can both be recommended for preventing IOP spikes after such surgery.

Comparative Evaluation of the Efficacy of the Bimatoprost 0.03%, Brimonidine 0.2%, Brinzolamide 1%, Dorzolamide 2%, and Travoprost 0.004%/Timolol 0.5%-Fixed Combinations in Patients Affected by Open-Angle Glaucoma

Purpose: This is a retrospective, comparative, head-to-head, not commissioned study about the efficacy of bimato-prost 0.03%, brimonidine 0.2%, brinzolamide 1%, dorzolamide 2%, and travoprost 0.004%/timolol 0.5%-fixed combinations in patients affected by na?ve open-angle glaucoma and IOP > 25 mmHg. Patients and Methods: Files from 70 patients (35 M, 35 F, mean age 69.52 y, S.D. 11.56, range: 37-87y) in our Glaucoma Service were retrospectively analyzed as long as 12 months. Every subgroup, including 14 age- and sex-matched patients, was allocated to 1 of the 5 groups of the fixed combinations monotherapy. Data recorded after 3 months follow-up were statistically analyzed by descriptive and ANOVA statistics as percentage of IOP reduction from baseline. Results: All the fixed combinations were effective in lowering IOP. The mean percentage reduction was: brimonidine/timolol 43.57%, dorzolamide/timolol 37.67%, bimatoprost/timolol 35.60%, travoprost/timolol 33.25% and brinzolamide/timolol 23.0%. The brimonidine/timolol fixed combination showed to be statistically significant more effective only than brinzolamide/timolol fixed combination (p = 0.001). Setting the α error to 5%, the power of the study is 26%, phi: 0.842. Discussion: In all this cohort of patients the target IOP was successfully achieved. All the fixed combinations used in this study had a very good profile of efficacy. Brimonidine, dorzolamide, bimatoprost and travoprost/timolol fixed combinations statistically significantly reduced the percentage of IOP from baseline (p = 0.001) more than brinzolamide/timolol fixed combination.

Sustained release of brimonidine from polydimethylsiloxane-coating silicone rubber implant to reduce intraocular pressure in glaucoma

Glaucoma is the leading cause of irreversible blindness,affecting 111 million people by 2040 worldwide.Intraocular pressure(IOP)is the only controllable risk factor for the disease and current treatment options seek to reduce IOP via daily taking eye drops.However,shortcomings of eye drops,such as poor bioavailability and unsatisfied therapeutic effects,may lead to inadequate patient compliance.In this study,an effective brimonidine(BRI)-loaded silicone rubber(SR)implant coated with polydimethylsiloxane(BRI@SR@PDMS)is designed and fully investigated for IOP reduction treatment.The in vitro BRI release from BRI@SR@PDMS implant reveals a more sustainable trend lasting over 1 month,with a gradually declined immediate drug concentration.The carrier materials show no cytotoxicity on human corneal epithelial cells and mice corneal epithelial cells in vitro.After administrated into rabbit’s conjunctival sac,the BRI@SR@PDMS implant releases BRI in a sustained fashion and effectively reduces IOP for 18 days with great biosafety.In contrast,BRI eye drops only maintain IOP-lowering effect for 6 h.Therefore,as a substitute of eye drops,the BRI@SR@PDMS implant can be applied as a promising non-invasive platform to achieve long-term IOP-lowering in patients suffering from ocular hypertension or glaucoma.

Intravitreal brimonidine inhibits formdeprivation myopia in guinea pigs

Background:The use of ocular hypotensive drugs has been reported to attenuate myopia progression.This study explores whether brimonidine can slow myopia progression in the guinea pig form-deprivation(FD)model.Methods:Three-week-old pigmented male guinea pigs(Cavia porcellus)underwent monocular FD and were treated with 3 different methods of brimonidine administration(eye drops,subconjunctival or intravitreal injections).Four different concentrations of brimonidine were tested for intravitreal injection(2μg/μL,4μg/μL,20μg/μL,40μg/μL).All treatments continued for a period of 21 days.Tonometry,retinoscopy,and A-scan ultrasonography were used to monitor intraocular pressure(IOP),refractive error and axial length(AL),respectively.On day 21,guinea pigs were sacrificed for RNA sequencing(RNA-seq)to screen for associated transcriptomic changes.Results:The myopia model was successfully established in FD animals(control eye vs.FD eye,respectively:refraction at day 20,0.97±0.18 D vs.−0.13±0.38 D,F=6.921,P=0.02;AL difference between day 0 and day 21,0.29±0.04mm vs.0.45±0.03 mm,F=11.655,P=0.004).Among the 3 different brimonidine administration methods,intravitreal injection was the most effective in slowing myopia progression,and 4μg/μL was the most effective among the four different concentrations of brimonidine intravitreal injection tested.The AL and the refraction of the brimonidine intravitreal injection group was significantly shorter or more hyperopic than those of other 2 groups.Fourμg/μL produced the smallest difference in AL and spherical equivalent difference values.FD treatment significantly increased the IOP.IOP was significantly lower at 1 day after intravitreal injections which was the lowest in FD eye of intravitreal injection of brimonidine.At day 21,gene expression analyses using RNA-seq showed upregulation of Col1a1 and Mmp2 expression levels by intravitreal brimonidine.Conclusions:Among the 3 different administration methods,intravitreal injection of brimonidine was the most effective in slowing myopia progression in the FD guinea pig model.Intravitreal brimonidine at 4μg/μL significantly reduced the development of FD myopia in guinea pigs.Expression levels of the Col1a1 and Mmp2 genes were significantly increased in the retinal tissues of the FD-Inj-Br group.

Clinical outcomes of combined versus separate carbachol and brimonidine drops in correcting presbyopia

Background:To test and compare in a masked fashion the efficacy of using a parasympathomimetic drug(3%carbachol)and an alpha-2 agonist(0.2%brimonidine)in both combined and separate forms to create optically beneficial miosis to pharmacologically improve vision in presbyopia.Methods:A prospective,double-masked,randomized,controlled clinical trial was conducted.Ten naturally emmetropic and presbyopic subjects between 42 and 58 years old with uncorrected distance visual acuity of at least 20/20 in both eyes without additional ocular pathology were eligible for inclusion.All subjects received 3%carbachol and 0.2%brimonidine in both combined and separate forms,3%carbachol alone and 0.2%brimonidine(control)alone in their non-dominant eye in a crossover manner with one week washout between tests.The subjects’pupil sizes and both near and distance visual acuities will be evaluated pre-and post-treatment at 1,2,4,and 8 h,by a masked examiner at the same room illumination.Results:Statistically significant improvement in mean near visual acuity(NVA)was achieved in all subjects who received combined 3%carbachol and 0.2% brimonidine in the same formula compared with those who received separate forms or carbachol alone or brimonidine alone(P<0.0001).Conclusion:Based on the data,the combined solution demonstrated greater efficacy than the other solutions that were tested.Improving the depth of focus by making the pupil small caused statistically significant improvement in near visual acuity,with no change in binocular distance vision.Trial registration:ACTRN12616001565437.Registered 11 November 2016.

Intravitreal brimonidine inhibits formdeprivation myopia in guinea pigs

Background:The use of ocular hypotensive drugs has been reported to attenuate myopia progression.This study explores whether brimonidine can slow myopia progression in the guinea pig form-deprivation(FD)model.Methods:Three-week-old pigmented male guinea pigs(Cavia porcellus)underwent monocular FD and were treated with 3 different methods of brimonidine administration(eye drops,subconjunctival or intravitreal injections).Four different concentrations of brimonidine were tested for intravitreal injection(2μg/μL,4μg/μL,20μg/μL,40μg/μL).All treatments continued for a period of 21 days.Tonometry,retinoscopy,and A-scan ultrasonography were used to monitor intraocular pressure(IOP),refractive error and axial length(AL),respectively.On day 21,guinea pigs were sacrificed for RNA sequencing(RNA-seq)to screen for associated transcriptomic changes.Results:The myopia model was successfully established in FD animals(control eye vs.FD eye,respectively:refraction at day 20,0.97±0.18 D vs.−0.13±0.38 D,F=6.921,P=0.02;AL difference between day 0 and day 21,0.29±0.04mm vs.0.45±0.03 mm,F=11.655,P=0.004).Among the 3 different brimonidine administration methods,intravitreal injection was the most effective in slowing myopia progression,and 4μg/μL was the most effective among the four different concentrations of brimonidine intravitreal injection tested.The AL and the refraction of the brimonidine intravitreal injection group was significantly shorter or more hyperopic than those of other 2 groups.Fourμg/μL produced the smallest difference in AL and spherical equivalent difference values.FD treatment significantly increased the IOP.IOP was significantly lower at 1 day after intravitreal injections which was the lowest in FD eye of intravitreal injection of brimonidine.At day 21,gene expression analyses using RNA-seq showed upregulation of Col1a1 and Mmp2 expression levels by intravitreal brimonidine.Conclusions:Among the 3 different administration methods,intravitreal injection of brimonidine was the most effective in slowing myopia progression in the FD guinea pig model.Intravitreal brimonidine at 4μg/μL significantly reduced the development of FD myopia in guinea pigs.Expression levels of the Col1a1 and Mmp2 genes were significantly increased in the retinal tissues of the FD-Inj-Br group.

α_2-肾上腺素能激动剂—阿法根的药理及临床研究进展

Brimonidine作为第三代高度选择性α2 肾上腺素能激动剂 ,自 1 996年开始在美国等 5 0多个国家以青光眼一线药物上市以来 ,经过 4年的临床使用证明 ,对治疗青光眼和高眼压症 ,无论单独用药或者联合用药均提供了高效和长期稳定的降压效果和安全性。它的降压效果优于贝特舒 ,与噻吗心安相似 ;安全性和耐受性方面优于噻吗心安。这一特点是由于其本身具有高度的α2 受体亲和性和较低的亲脂性的结果 ,其降压机制是减少房水生成和增加房水经脉络膜巩膜外引流的作用。Brimonidine在治疗青光眼中的重要独特的视网膜神经节细胞的保护作用由实验动物模型证实 。

Intraocular pressure-lowering effects of commonly used fixed combination drugs with timolol in the management of primary open angle glaucoma

AIM:To evaluate intraocular pressure(IOP)-lowering effect and ocular tolerability of brimonidine/timolol,dorzolamide/timolol and latanoprost/timolol fixed combination therapies in the management of primary open angle glaucoma.· METHODS:Each drug was administered for two months, after which a circadian tonometric curve was recorded using a Goldmann applanation tonometer.Ocular discomfort(conjunctival hyperemia, burning or stinging, foreign body sensation, itching, ocular pain) of each eye was assessed by the subject on a standardized ocular discomfort scale.RESULTS:Among the three study groups, there were no significant differences in the mean baseline IOP measurements, mean 2ndmo IOP measurements, and mean(%) change of IOPs from baseline. Among the three study groups, there were no significant differences in the mean IOP measurements obtained at circadian tonometric curves at baseline and at two months controls. In sum brimonidine/timolol, dorzolamide/timolol and latanoprost/timolol fixed combination therapies showed similar effects on IOP levels.· CONCLUSION:Brimonidine/timolol, dorzolamide/timolol and latanoprost/timolol fixed combination therapies showed similar lowering efficaties on IOP levels whereas there was no any difference between each other.

Intraocular pressure with rebound tonometry and effects of topical intraocular pressure reducing medications in guinea pigs

AIM： To investigate the intraocular pressure（IOP） of adult guinea pig eyes with rebound tonometry（RBT）,and assess the effects of four distinctive topical IOP reducing medications including Carteolol,Brimonidine,Brinzolamide and Latanoprost.METHODS： The IOPs of twenty-four 12-week-old guinea pigs（48 eyes） were measured every two hours in one day with RBT as baselines.All the animals were then divided into four groups（Carteolol,Brimonidine,Brinzolamide and Latanaprost groups,n=6）.The IOPs were measured and compared to the baseline 1,2,3,5,7,9,15 and 24 h after treatment.RESULTS： The mean baseline IOP of 24 guinea pigs（48 eyes） was 10.3±0.36 mm Hg（6-13 mm Hg） and no binocular significant differences of IOPs were observed（t=1.76,P〉0.05）.No significant difference of IOP in Carteolol group at each time point was observed before and after treatment（t=1.48,P〉0.05）.In Brimonidine group,IOP was 2.2±1.9 mm Hg lower than the baseline after one hour（t=3.856,P=0.003） and lasted for one hour.In Brinzolamide group,IOP was 1.4±1.1 mm Hg lower than the baseline after one hour（t=4.53,P=0.001） and lasted for 7h and the IOP declined most at 3h.In Latanaprost group,IOP was 2.1±1.3 mm Hg lower than the baseline after one hour（t=6.11,P=0.001） and lasted for one hour.CONCLUSION： The IOP of guinea pig eyes is relatively stable compared to human eyes.In four reducing IOP medications,no significant effect of Carteolol is observed.Brinzolamide has the longest duration,while the Brimonidine has the shortest duration and the maximum level of treatment.

Management of glaucoma in pregnancy:risks or choices,a dilemma?

The treatment of glaucoma in and around pregnancy offers the unique challenge of balancing the risk of vision loss to the mother as against the potential harm to the fetus or newborn. Most anti-glaucoma drugs（i.e.beta-blockers, prostaglandin analogues, carbonic anhydrase inhibitors topical and systemic, cholinergics,anticholinesterases, and apraclonidine） are considered category C agents and ophthalmologists are usually limited to treating patients with the category B drugs of brimonidine and dipivefrin. Brimonidine is generally the preferred first-line drug in the first, second and early third trimester. Late in the third trimester, brimonidine should be discontinued because it can induce central nervous system depression in newborns wherein topical carbonic anhydrase inhibitors may be the optimal choice.Glaucoma surgery can be performed with caution in second and third trimester if the patients have a strong indication for the procedure. However, anesthetics,sedative agents, and antimetabolites still have potential risk for the fetus. Argon laser trabeculoplasty（ALT） or selective laser trabeculoplasty（SLT） is an alternative treatment that can be performed in all trimesters.Carbonic anhydrase inhibitors and β-blockers are certified by the American Academy of Pediatrics for use during nursing. However, low doses of these medications should be considered when used in the breast feeding period. Optimum treatment for glaucoma in pregnancy must not be withheld so as to prevent any further deterioration in progressive vision loss and quality of life.

A smart simple spectrophotometric method for simultaneous determination of binary mixtures

A new simple spectrophotometric method was developed for the simultaneous determination of drugs with interfering spectra in binary mixtures without previous separation. The new method is based on a simple modification for the ratio subtraction method. This modification enabled wider range of application. The proposed ratio difference method was applied for the determination of brimonidine and timolol in laboratory prepared mixtures with mean percentage recoveries 100.40±2.29 and 101.23± 1.30 respectively, and in their pharmaceutical formulation with mean percentage recoveries 101.08±0.44 and 100.66±0.52 respectively. The suggested ratio difference method was validated according to USP guidelines and can be applied for routine aualitv control testing.

A 4-year retrospective study of add-on therapy to the fixed combination of dorzolamide/timolol for the treatment of POAG

AIM:To evaluate the long-term response to the fixed combination of dorzolamide/timolol in patients with primary open angle glaucoma(POAG)and the addition of other intraocular pressure(IOP)lowering medications such as prostaglandin analogs and brimonidine.METHODS:A retrospective,non-randomized,and descriptive clinical study was performed with 182 eyes diagnosed with POAG.Patients were divided into three groups:a group with fixed combination of dorzolamide/timolol only,a second group with prostaglandin analogs plus fixed combination of dorzolamide/timolol,and a third group with the addition of brimonidine to the same fixed combination.IOP data were gathered retrospectively and the differences between groups were calculated.RESULTS:IOP was reduced satisfactorily in all three groups;however,a progressive IOP reduction was noted in the group with the fixed combination plus prostaglandin analogs.In this group,a progressive,significant and more homogeneous response of the reduction was noted in comparison with the other groups.CONCLUSION:IOP reduction was efficacious in all three groups.The addition of prostaglandin analogs showed progressive IOP reduction,progressive responseand absence of long-term drift.Brimonidine did not show a significant additive effect.

Drug-loaded chitosan film prepared via facile solution casting and air-drying of plain water-based chitosan solution for ocular drug delivery

Chitosan is a nature-based polymer with low toxicity,excellent biocompatibility and biodegradability.However,the intractable solubility of chitosan in water and most conventional solvents hampers its biomedical applications.Following the dissolution method for dissolving chitosan in plain water developed by us,chitosan was dissolved in ionic liquid followed by overnight freezing at−20℃ and subsequent solvent exchange with plain water at room temperature.In this study,we fabricated a drug-carrying chitosan film via solution casting and air-drying by using the plain water-based chitosan solution.Specifically,brimonidine tartrate(BT),an antiglaucoma drug,was dissolved in the plain-water based solution and used to prepare BT-loaded chitosan film,i.e.,chitosan-BT film.The resulting film is transparent,structurally stable,and mucoadhesive.Micro-sized antiglaucoma BT drug crystals form and are well dispersed in the chitosan film.The chitosan-BT film enables BT to have a high corneal permeability with fast drug release kinetics for potential ocular drug delivery.