最新型局部碳酸酐酶抑制剂派立明的临床前及临床研究

派立明是一种最新型的局部碳酸酐酶抑制剂。此药可选择性、高亲和力及明显地抑制碳酸酐酶同功酶Ⅱ的活性,有效地降低眼压。本品滴眼后可快速进入眼组织,在虹膜、睫状体、脉络膜、视网膜、晶状体和血液中有较长的半衰期(数天)。虽然用派立明滴眼后,可在全血中测出药物浓度,提示陔药可全身吸收,但主药和其代谢产物的血浆浓度非常低,在稳定状态下药物与红细胞内碳酸酐酶的结合达不到完全饱和。因此,不会出现全身酸中毒或其他与口服碳酸酐酶抑制剂有关的副作用。对兔眼滴用派立明还町增加视乳头血流量,而对全身酸碱平衡的影响极小。如这一作用在人眼被证实,将对有视神经病变的青光眼患者十分有益。1％派立明每日滴眼2次的降眼压效果最好,且患者的耐受性较多佐胺好,这可提高患者长期用药的依从性。滴眼后最常见的剐作用是视物模糊(6％)及口苦、口酸等味觉异常(6％),总之,派立明的降眼压作用强,副作用小,滴眼舒适,患者耐受性好,是一种非常有价值的抗青光眼新药。     

Effects of brinzolamide on ocular haemodynamics in healthy volunteers

AIM: A prospective, randomised study to evaluate effects of brinzolamide on ocular haemodynamics in healthy volunteers. METHODS: 30 volunteers (12 men, 18 women; 28.3 (SD 7.8) years) were prospectively randomised to either brinzolamide or placebo during a 2 week double masked treatment trial. Examinations were performed at baseline and after 2 weeks of treatment. Intraocular pressure was measured and automatic static perimetry (Humphrey field analyser, 24-2) and contrast sensitivity (CSV 1000, Vector Vision) were performed. Retrobulbar blood flow velocities (peak systolic and end diastolic velocity) and resistive indices (RI) of ophthalmic artery, central retinal artery and of temporal and nasal short posterior ciliary arteries were measured by colour Doppler imaging (Sonoline Sienna Siemens). In video fluorescein angiograms (scanning laser ophthalmoscope, Rodenstock) arteriovenous passage time (AVP, dilution curves) and peripapillary diameters of retinal arterioles and venules were measured by means of digital image analysis. RESULTS: Intraocular pressure was significantly decreased by brinzolamide (p<0.0001). Neither brinzolamide nor placebo changed visual field global indices after treatment. Contrast sensitivity at 3 cycles per degree was significantly higher in the placebo group (p<0.05). Apart from an increase of RI in ophthalmic artery under placebo treatment (p<0.05) there was no effect in retrobulbar haemodynamics in both groups. Brinzolamide therapy alone resulted in a significant reduction of AVP compared to baseline (p<0.05), while peripapillary retinal vessels diameters remained unaffected. CONCLUSIONS: Apart from the expected decrease of intraocular pressure brinzolamide showed no significant change in retrobulbar haemodynamics, but a significant shortening of AVP. Since in glaucoma AVP is prolonged indicating vascular dysfunction this effect might be beneficial in glaucoma therapy.     

Efficacy of topical brinzolamide in children with retinal dystrophies

ABSTRACT

Background: Inherited retinal dystrophies are a leading cause of irreversible blindness in children in the United States. Topical carbonic anhydrase inhibitors have improved central vision and cystoid macular edema in patients with retinal dystrophies, but few studies have assessed their efficacy in children.

Materials and Methods: A retrospective chart review was performed with Institutional Review Board approval to identify pediatric patients with inherited retinal dystrophies who received topical brinzolamide at a single university center between 2008 and 2015. Serial visual acuity and central macular thicknesses were compared to assess the efficacy of brinzolamide.

Results: Seven subjects were identified who met the inclusion criteria. Four had juvenile X-linked retinoschisis, two had retinitis pigmentosa, and one had Leber congenital amaurosis. All were prescribed brinzolamide thrice daily; however, one patient was completely non-compliant. Four of the six treated patients exhibited a mild decrease in central macular thickness in both eyes during the study with all six treated patients having significantly improved vision at the first endpoint, 33.2 ± 8.2 months after treatment initiation. For treated patients, average visual acuity (LogMAR) ± standard error of the mean improved from 0.5 ± 0.04 pre-treatment to 0.3 ± 0.1 at the second endpoint, 50.2 ± 7.3 months after treatment initiation.

Conclusions: Mild anatomic improvement of macular cysts was seen in pediatric patients using brinzolamide. Visual acuity improvement occurred even without significant reduction in macular cysts. Further studies are needed to determine whether the beneficial effects of carbonic anhydrase inhibitors are sustained in children with inherited retinal degenerations.     

Retinal peripapillary blood flow before and after topical brinzolamide

PURPOSE: To study the effect of topical brinzolamide on retinal capillary blood flow by the Heidelberg Retina Flowmeter (HRF) in patients with glaucoma. METHODS: Twenty patients with glaucoma were consecutively recruited. One eye for each patient was randomly selected. Patients were classified as glaucomatous if they had an abnormal visual field and/or an abnormal optic nerve head with an intraocular pressure (IOP) greater than 21 mm Hg without any treatment. After an eye examination, baseline retinal blood flow measurements were made with confocal scanning laser Doppler flowmetry. Blood flow and IOP measurements were then repeated after 1 month of treatment. Blood flow measurements were analyzed by using an automatic full-field perfusion image analysis (AFFPIA) program. The blood flow was calculated in the superior and inferior part of the optic disk. In each area, the blood flow was calculated as temporal area, the nasal area and the rim area as for software AFFPIA. RESULTS: The mean age of the patients was 56 +/- 7 (mean +/- standard deviation) years. The mean IOP before treatment was 23.7 +/- 1.5 mm Hg while the mean IOP after 4 weeks of treatment was 19.1 +/- 2.2 mm Hg. This difference was statistically significant (p < 0.01). Significant (p < 0.05) increases in retinal blood flow were found for the temporal and nasal areas between baseline and 1 month after the treatment. No difference was found between superior and inferior sectors. CONCLUSION: Topical brinzolamide reduced the IOP significantly and apparently improved retinal blood flow as measured by the HRF.     

Short-term effect of topical brinzolamide on human central corneal thickness

PURPOSE. To investigate the effect of short-term brinzolamide application on human central corneal thickness (CCT). METHODS. Seventeen eyes of 16 patients who underwent neodymium:YAG laser posterior capsulotomy were included in the study group. Twenty-two subjects served as controls. Brinzolamide twice daily and fluorometholone four times daily were initiated after the procedure. Corneal thickness was evaluated with an ultrasound pachymetry from the central region. CCT measurements were performed before the procedure, at first day, and at the end of first week. RESULTS. The mean baseline CCT value was 535.1+/-37.8 micronm. In comparison to the control group (546.4+/-22.2 micronm), there was no statistically significant difference (p=0.248). After brinzolamide instillation, the mean CCT values at first day and at first week was measured as 545.1+/-40.1 micronm and 538.8+/-39.4 micronm, respectively. The difference at first day was statistically significant when compared to the baseline values (p=0.00017). When compared to the control group, no statistically significant difference was observed for the mean CCT values of the first day and first week (p=0.906 and p=0.484, respectively). In the fellow eyes, mean CCT values increased following the dorzolamide instillation (529.3+/-42.6 micronm, 534+/-41.7 micronm, and 533+/-41.9 micronm, respectively). No statistically significant difference was observed between the control group and fellow eye group when compared (p=0.162, p=0.247, p=0.270, respectively). CONCLUSIONS. Brinzolamide may cause a short-term increase in the human CCT, particularly on the first day.     

Therapy of normal tension glaucoma: effect of brinzolamide on ocular haemodynamics

BACKGROUND: Altered ocular perfusion plays a role in the pathophysiology of normal tension glaucoma. Dorzolamide, a locally applied inhibitor of carbonic anhydrase, is thought to increase ocular blood flow. Less data are available regarding the influence exercised on ocular perfusion by brinzolamide, another and different, locally administered, inhibitor of carbonic anhydrase. PATIENTS AND METHODS: n = 15 eyes of 8 normal tension glaucoma patients were subjected to colour Doppler imaging and Langham-OBF (LOBF) before and during a therapy for 3 - 5 weeks with brinzolamide. RESULTS: Brinzolamide reduces intraocular pressure from 15.8 +/- 0.9 to 12.6 +/- 0.9 mm Hg (n = 15; P < 0.05). Systolic as well as diastolic blood flow velocities, resistive (RI) and pulsatility index (PI), measured by CDI, remained unchanged in the presence of brinzolamide. LOBF values are also not influenced by brinzolamide (1014 + 115 before vs. 1113 +/- 178 microl under therapy; n = 15; n. s.). DISCUSSION: Brinzolamide does not exercise any impact on ocular haemodynamics. This is different from the properties of dorzolamide that had been reported previously.     

Medical control of intraocular pressure with brinzolamide 1% after phacoemulsification

Background: To compare the effectiveness of only 1 drop of topical brinzolamide 1% with dosing every 12 hours and with no ocular hypotensive medication following clear corneal phacoemulsification surgery.Methods: This prospective, randomized, double-blind study was composed of 60 eyes of 60 patients who underwent uneventful clear corneal phacoemulsification surgery under topical anesthesia. There were no intraoperative complications. Eyes were randomized to receive only 1 drop of topical brinzolamide 1% immediately after surgery, 1 drop of brinzolamide 1% every 12 (q12h) hours starting immediately after speculum removal, or no ocular hypotensive medication (control group). Intraocular pressure (IOP) was measured preoperatively and at 4 to 6 hours and 18 to 24 hours postoperatively by a Perkins tonometer.Results: Preoperative IOP was not significantly different among the 3 groups. IOPs of both the brinzolamide 1 drop group (p = 0.000) and the brinzolamide q12h group (p = 0.001) were significantly lower than those of the control group at 4 to 6 hours postoperatively. The same result was observed at 18 to 24 hours postoperatively in the brinzolamide q12h group (p = 0.001) but not the brinzolamide 1 drop group (p = 0.489). The brinzolamide q12h group had significantly lower IOP compared with the brinzolamide 1 drop group (p = 0.000) at 18 to 24 hours postoperatively. None of the eyes in the medication groups, but 1 eye (5%) in the control group, had postoperative IOP elevation ≥30 mm Hg at 4 to 6 hours; such an elevation was not encountered at postoperative 18 to 24 hours. Preoperative to postoperative IOP increase of >5 mm Hg at 4 to 6 hours postoperatively was seen in 4 (20%), 4 (20%), and 14 (70%) eyes in the brinzolamide 1 drop group, the brinzolamide q12h group, and the control group, respectively.Interpretation: The current study reveals that 1 drop of brinzolamide 1% is sufficient to control IOP within the first 4 to 6 hours following uneventful phacoemulsification, whereas 12-hour dosing is necessary for prolonged control of IOP.     

Effects of brinzolamide on aqueous humor dynamics in monkeys and rabbits.

This study examines the mechanisms by which brinzolamide reduces intraocular pressure (IOP) in healthy rabbits and in monkeys with unilateral ocular hypertension. Intraocular pressures were measured by pneumatonometry and aqueous flow was determined by fluorophotometry before and after three twice-daily drops of 1% brinzolamide to both eyes per monkey and after similar treatment to one eye per rabbit. In monkeys, outflow facility was determined by fluorophotometry and uveoscleral outflow was calculated. In rabbits, outflow facility was determined by two-level constant pressure infusion and uveoscleral outflow was measured by an intracameral tracer technique. Compared with contralateral vehicle-treated rabbit eyes, IOP was reduced in brinzolamide-treated eyes by 2.5 +/- 1.9 mmHg (mean +/- standard deviation; p =.006) at four hours after the second dose. Aqueous flow was reduced by 0.50 +/- 0.65 microl/min (p =.02). This effect was found in rabbits previously treated with brinzolamide but not in naive rabbits. Treated hypertensive eyes of monkeys had a reduction in IOP of 7.3 +/- 8.8 mmHg (p = 0.01) and aqueous flow of 0.69 +/- 1.10 microL/min (p = 0.05) when compared with baseline. Brinzolamide did not affect outflow facility or uveoscleral outflow in either rabbits or monkeys. It is concluded that, in normotensive eyes of rabbits and hypertensive eyes of monkeys, brinzolamide reduces IOP by reducing aqueous flow and not by affecting aqueous humor drainage.     

Timolol versus brinzolamide added to travoprost in glaucoma or ocular hypertension

Background  

To compare the efficacy and safety of timolol 0.5% versus brinzolamide 1.0% when added to travoprost monotherapy in patients with primary open-angle glaucoma or ocular hypertension.     

Effect of brinzolamide and dorzolamide on aqueous humor flow in human eyes.

PURPOSE: To measure the relative efficacy of brinzolamide hydrochloride 1% ophthalmic suspension, a new carbonic anhydrase inhibitor, compared with the currently used dorzolamide hydrochloride 2% ophthalmic solution as suppressors of aqueous humor flow in human eyes, and to study the difference of effect during the day and at night. METHODS: A randomized, double-masked, placebo-controlled study of 25 normal human subjects was carried out at Mayo Clinic. The daytime rate of aqueous humor flow was measured every 2 hours from 8 AM to 4 PM by means of fluorophotometry. Likewise, the night-time rate of aqueous humor flow was measured every 2 hours from 12 AM to 6 AM. Intraocular pressure was measured at 4 PM and 6 AM. RESULTS: Brinzolamide reduced aqueous flow by 0.47+/-0.20 microl per min (mean+/-SD) during the day, whereas dorzolamide reduced flow by 0.34+/-0.20 microl per min. Brinzolamide reduced aqueous flow by 0.16+/-0.12 microl per min during the night, whereas dorzolamide reduced flow by 0.10+/-0.13 microl per min. Brinzolamide reduced afternoon intraocular pressure by 1.5+/-1.1 mm Hg, and dorzolamide reduced afternoon intraocular pressure by 1.1+/-1.0 mm Hg. Brinzolamide reduced the morning awakening intraocular pressure by 0.3+/-1.6 mm Hg, and dorzolamide reduced it by 0.8+/-1.0 mm Hg. CONCLUSIONS: Our data support the idea that brinzolamide is at least as efficacious as dorzolamide as a suppressor of aqueous humor flow in normal human eyes and that there is probably not a clinically significant difference between the two drugs in this efficacy. Clinicians who prescribe brinzolamide should expect similar ocular hypotensive responses from brinzolamide and dorzolamide.     

Effects of brinzolamide on rabbit ocular blood flow in vivo and ex vivo

AIM: To investigate if significant improvement of optic disc blood flow (ODBF) occurs after instillation of brinzolamide onto rabbit eyes. METHODS: Testing of bilateral intraocular pressure (IOP) and left ODBF in 10 male rabbits took place every 3h over a 24h period. Brinzolamide (1% ophthalmic solution, two drops at 9:00 and 21:00) was administered to the left eye. ODBF, assessed using laser speckle flowgraphy, was determined as the mean blur rate (MBR). Furthermore, the effect of brinzolamide on isolated rabbit ciliary arteries using isometric tension recording system was performed. RESULTS: After brinzolamide instillation, IOP was significantly decreased in the left eye. MBR-vessel was greater at 18:00 and 21:00 (P<0.05) than in the controls. MBR-tissue and MBR-average were greater at 18:00 (P<0.05) than in the controls. For isolated arteries pre-contracted with a high-K solution, brinzolamide induced concentration-dependent relaxation, reaching 46.1%±9% (n=21) at 1 mmol/L. In Ca2+-free solutions, incubation with brinzolamide suppressed 1 μmol/L histamine-induced contractions (P<0.05). CONCLUSION: Brinzolamide decreases IOP and increases ocular blood flow. The direct vasodilatory effect of brizolamide is mediated by suppression of Ca2+ release from intracellular calcium stores.     

Comparing the effects of travoprost and brinzolamide on intraocular pressure after phacoemulsification

PURPOSE: To evaluate the intraocular pressure (IOP) lowering effect of travoprost and brinzolamide within the first 24 h after phacoemulsification cataract surgery. METHODS: This prospective, randomized, double-masked, controlled study comprised 90 eyes of 90 consecutive patients with senile cataract who had uneventful phacoemulsification surgery. Eyes in the first group received travoprost 0.0015%, second group received brinzolamide 1%. Eyes in the third group received balanced salt solution and were used as control. One drop was instilled immediately after surgery. IOP was measured 24 h preoperatively, 6 and 24 h postoperatively. Analysis of variance, Student's-t and chi2-tests were used for statistical analyses. RESULTS: Preoperatively IOP was not significantly different among the three groups (P = 0.653). At 6 and 24 h postoperatively IOP was lower in both travoprost and brinzolamide group when compared to control group (P = 0.018 and 0.015 at 6 h, P = 0.010 and 0.007 at 24 h between travoprost and brinzolamide group was not significant (P = 0.744 at 6 h and P = 0.672 at 24 h). CONCLUSION: Both travoprost and brinzolamide significantly lowered IOP after small incision phacoemulsification cataract surgery within the first 24 h without any side effect.     

Preclinical safety of anecortave acetate

A number of preclinical safety pharmacology and toxicity studies have been performed on the angiostatic cortisene anecortave acetate in various species and using different routes of administration (oral, intravenous, subcutaneous, topical ocular, intraocular injection, posterior juxtascleral) and a wide range of doses (0-1,000 mg/kg). Anecortave acetate did not interact with a broad panel of pharmacological receptors and had no apparent pharmacological effects on major organ systems including the central nervous, gastrointestinal, renal, cardiovascular, and respiratory systems. Oral, topical ocular, and posterior juxtascleral administration of anecortave acetate had no significant ocular or systemic side effects or toxicity. In addition, there was no significant carcinogenic or reproductive/developmental toxicity associated with anecortave acetate in genotoxicity, carcinogenicity, and reproductive toxicity studies.     

Preclinical efficacy of anecortave acetate

Anecortave acetate is a unique ocular angiostatic cortisene that has broad-based anti-angiogenic activity in 14 different preclinical models of neovascularization, across multiple species and inducers of neovascularization. Anecortave acetate is being tested clinically for inhibition of choroidal neovascularization associated with age-related macular degeneration.     

Fixed-combination brinzolamide 1%/brimonidine 0.2% vs monotherapy with brinzolamide or brimonidine in patients with open-angle glaucoma or ocular hypertension: results of a pooled analysis of two phase 3 studies

Purpose

To describe pooled efficacy and safety data from two phase 3 studies comparing brinzolamide 1%/brimonidine 0.2% fixed combination (BBFC) with its component medications, brinzolamide and brimonidine, in patients with open-angle glaucoma or ocular hypertension.

Methods

Data were pooled from two nearly identical clinical trials comparing BBFC with its component medications, each given three times daily. The 3-month efficacy outcome was mean intraocular pressure (IOP) at 0800, 1000, 1500, and 1700 hours. Safety outcomes included adverse events (AEs), best-corrected visual acuity, examination of ocular structures, pachymetry, perimetry, and vital signs.

Results

A total of 1350 patients were enrolled and included in this analysis (BBFC, n=437; brinzolamide, n=458; brimonidine, n=455). Baseline mean IOP levels were similar among the three treatment groups. At 3 months, mean IOP of the BBFC group was significantly lower than that of either monotherapy group (P<0.0001) at all the four time points. A total of 272 patients (20.1%) experienced at least one treatment-related AE (BBFC, 24.6% brinzolamide, 18.7% brimonidine, 17.4%), the majority of which were ocular AEs. One serious AE, moderate intensity chest pain, was considered related to brinzolamide treatment and resulted in study discontinuation.

Conclusions

This analysis strengthens the conclusions drawn from the two individual phase 3 studies showing that, in patients with open-angle glaucoma or ocular hypertension, BBFC had significantly superior IOP-lowering activity compared with either brinzolamide or brimonidine alone and a safety profile consistent with that of its individual components.     

噻吗洛尔和布林佐胺联合曲伏前列素治疗原发性开角型青光眼与高眼压患者的临床研究

目的比较噻吗洛尔和布林佐胺辅助曲伏前列素治疗原发性开角型青光眼(primary open-angle glaucoma,POAG)或高眼压(ocular hypertension,OHT)患者的效果。方法将使用曲伏前列素单剂药物治疗6周后眼压>18mmHg(1kPa=7.5mm-Hg)的POAG及OHT患者随机分为治疗组和对照组。治疗组40例(40眼)加入10g·L-1布林佐胺滴眼液(每日2次),对照组40例(40眼)加入5g·L-1噻吗洛尔滴眼液(每日2次)。随访2周、8周、14周、20周、26周的眼压、血压、心率,观察眼部症状和体征,26周检测与基线对应的相关参量,包括视野、视觉电生理、视网膜神经纤维层厚度、视盘盘沿面积、泪液功能等。计算26周时眼压≤18mmHg患者百分比。结果两组眼压与基线比较均有明显下降,差异均有显著统计学意义(均为P<0.01)。治疗组降眼压持续平稳,对照组眼压于20周后出现上升趋势。24h眼压描记显示治疗组降眼压稳定,昼夜眼压平稳,对照组夜间眼压控制欠佳。2组对患者血压无影响,治疗组对患者心率无影响,对照组在联合用药20周始出现心率抑制。联合用药后对照组视野光敏感度下降,泪膜稳定性下降,治疗组无明显异常。治疗组常见的副作用是眼部刺激症状、味觉异常、口干等,对照组副作用是眼异物感、干涩等。结论曲伏前列素单剂治疗不足时,添加布林佐胺和噻吗洛尔均能进一步降低眼压,布林佐胺长期及短期眼压波动幅度均比噻吗洛尔小,局部及全身副作用小。