Timolol activates the enzyme activities of human carbonic anhydrase I and II.

Timolol, a beta-blocker, has been shown to be an effective ocular hypotensive agent when used alone or with carbonic anhydrase inhibitor on ocular hypertensive or open angle glaucoma patients. The effect of timolol hemihydrate on the CO(2) hydration activities of human carbonic anhydrase (HCA) I and II and their reaction mechanisms were investigated. Timolol activates the enzyme activities of HCA I and HCA II. In HCA I and II, the enzyme kinetic results clearly showed that timolol increases the value of V(max) but does not influence the value of K(m). The enzyme kinetic method showed that timolol noncompetitively activates HCA I and II activities through the formation of a ternary complex consisting of the enzyme, the substrate, and timolol. These results indicate that timolol binds apart from the narrow cavity of the active site. AutoDocking results showed that timolol binds at the entrance of the active site cavity in a region where the proton shuttle residue, His 64, of HCA I or II, is placed. The enzyme kinetic and AutoDocking results showed that timolol might weakly bind near the proton shuttle residue, His 64, to accelerate the proton transfer rate from His 64 to the buffer components. It is known that efficient activators of carbonic anhydrase possess a bulky aromatic/heterocyclic moiety and a primary/secondary amino group in their molecular structure. Timolol has a heterocyclic moiety and a secondary amino group, which are typical structures in efficient activators of carbonic anhydrase.

Recovery of reliability by retest after a 5-minute interval in frequency doubling technology perimetry.

PURPOSE: In frequency doubling technology (FDT) perimetry, the incidence of tests classified as unreliable is higher in the second-tested left eye than in the first-tested right eye when perimetry is performed without a rest period. The purpose of this study was to determine whether the incidence of unreliable results was reduced when the retest began after a 5-min rest period. METHODS: The subjects were 978 residents of Miyoshi City, Japan, who underwent FDT perimetry during a medical checkup. FDT perimetry was always performed first on the right eye and then on the left eye without a rest interval. When the results were determined to be unreliable, FDT perimetry was repeated after a 5-min rest interval. RESULTS: The perimetric results were determined to be unreliable in one eye of 119 subjects; the results of the first-tested right eye were unreliable in 24 (20.2%), and the results of the second-tested left eye were unreliable in 95 (79.8%) subjects. This difference in the incidence of reliability was significant (P<0.001). After a 5-min rest interval, the percentage of eyes with reliable results recovered to 92% of the right eyes and to 86% of the left eyes. CONCLUSIONS: The incidence of unreliable results in FDT perimetry of the second-tested left eye was higher than that of the first-tested right eye when tests were performed without a rest interval. However, the incidence of unreliability in the eye was decreased when the retest was performed after a 5-min rest interval.

Prevalence of glaucoma in adults with Down's syndrome.

PURPOSE: To compare the prevalence of glaucoma in adults with Down's syndrome (DS) to that in non-DS control adults. METHODS: Twenty-six patients (14 men and 12 women) with DS and 188 control subjects (105 men and 83 women) were studied. The mean age was 35.1 +/- 6.9 (+/- SD) years in the DS group and 36.9 +/- 5.2 years in the control group. There were no significant differences in age or sex distribution between the two groups. Glaucoma was diagnosed by two glaucoma specialists based on the optic disc findings obtained through dilated pupils. RESULTS: The prevalence of patients with glaucoma in the DS group was 11.5%, significantly higher (P = 0.014) than that in the control group, 1.1%. There was no significant difference in intraocular pressure between glaucomatous eyes (12.2 +/- 3.2 mmHg) and nonglaucomatous eyes (11.1 +/- 4.1 mmHg) in the DS group (P = 0.465). CONCLUSIONS: The prevalence of glaucoma in adult patients with DS was significantly higher than that in age-matched control subjects.

Pathogenesis of macular edema with branch retinal vein occlusion and intraocular levels of vascular endothelial growth factor and interleukin-6.

PURPOSE: To determine whether correlations between vascular endothelial growth factor (VEGF) or interleukin-6 (IL-6) contribute to the pathogenesis of macular edema in eyes of patients with branch retinal vein occlusion (BRVO). DESIGN: Retrospective case-control study. METHODS: Nineteen patients with macular edema with BRVO and seven patients with non-ischemic ocular disease (control group) were studied. The degree of retinal ischemia was evaluated in terms of the area of capillary non-perfusion, and the severity of macular edema was examined by optical coherence tomography. Aqueous humor samples were obtained at the time of combined vitrectomy and cataract surgery, and VEGF and IL-6 levels in aqueous humor and plasma were determined by enzyme-linked immunosorbent assay. RESULTS: Aqueous levels of VEGF (351 +/- 273 pg/ml) and IL-6 (7.10 +/- 6.51 pg/ml) were significantly elevated in patients with BRVO compared with the control patients (119 +/- 38.7 pg/ml and 2.27 +/- 1.11 pg/ml, respectively) (P = .0017 and P = .0052, respectively). Aqueous level of VEGF was significantly correlated with that of IL-6 (P = .0396), and aqueous levels of VEGF and IL-6 were correlated with the size of the BRVO non-perfused area (P < .0001 and P = .0331, respectively). Aqueous level of VEGF was correlated with the severity of macular edema (P = .0306). CONCLUSIONS: VEGF and IL-6 may be involved in the pathogenesis of macular edema with BRVO. The increase in these cytokines might be used as a unique index of BRVO, through which we can determine the severity of the ischemic condition as being in a quiescent state or an exacerbation of macular edema.

The efficacy and ocular discomfort of substituting brinzolamide for dorzolamide in combination therapy with latanoprost, timolol, and dorzolamide.

PURPOSE: The aim of this study was evaluate the efficacy and ocular discomfort of substituting brinzolamide for dorzolamide in patients with glaucoma treated by latanoprost, timolol, and dorzolamide. METHODS: An 8-week, prospective, randomized, open-label, comparative study was performed in 58 patients with primary open-angle glaucoma treated by latanoprost, timolol, and dorzolamide. These patients were randomly enrolled into two groups: (1) dorzolamide three times daily was substituted with brinzolamide twice-daily (substituting group); and (2) dorzolamide three times daily was continued (control group). Intraocular pressure (IOP) was measured at baseline, 4, and 8 weeks after the enrollment. Subjective ocular discomfort (irritation and blurred vision) at the time of the instillation of the patient was noted with interview. RESULTS: The IOPs at baseline, 4 and 8 weeks after the enrollment were 17.7 +/- 2.7 mmHg, 17.5 +/- 2.6 mmHg, and 17.4 +/- 2.9 mmHg in the substituting group, and 18.0 +/- 2.5 mmHg, 17.8 +/- 2.5 mmHg, and 17.9 +/- 2.6 mmHg in the control group, respectively. There were no significant differences in IOP changes between the two groups (P = 0.74). In the substituting group, ocular irritation was decreased significantly (P = 0.0014) from 63% to 20%. The slight increase of blurred vision from 27% to 37% that occurred in the substituting group was not significant (P = 0.58). In the control group, neither ocular irritation (P = 0.58, from 68% to 57%) nor blurred vision (P = 0.99, from 25% to 21%) was changed. CONCLUSIONS: Substituting brinzolamide for dorzolamide maintained stable IOP with improvement in ocular comfort in patients with glaucoma.

The efficacy and safety of topical brinzolamide and dorzolamide when added to the combination therapy of latanoprost and a beta-blocker in patients with glaucoma.

PURPOSE: Brinzolamide and dorzolamide are often used as adjunctive therapy to other antiglaucoma agents. The purpose of this study was to compare the efficacy and safety of brinzolamide 1% versus dorzolamide 1% when added to the combination therapy of latanoprost and a beta-blocker in patients with glaucoma. METHODS: An 8-week, randomized, open-label comparative study was performed in 52 patients with glaucoma. Brinzolamide 1% (twice a day) or dorzolamide 1% (3 times a day) was randomly administered to the patients who had been treated with both latanoprost and a betablocker. RESULTS: Intraocular pressure (IOP) were both decreased significantly (P < 0.0001) from 18.6 +/- 2.3 mmHg to 16.7 +/- 2.3 mmHg and from 18.4 +/- 2.6 mmHg to 16.6 +/- 2.5 mmHg, respectively, 8 weeks after the addition of brinzolamide or dorzolamide. However, the difference between the groups was not significant (P = 0.86). The incidence of ocular irritation was significantly higher (P < 0.0001) in the dorzolamide group (74%) than the brinzolamide group (16%), but there was no significant difference in blurred vision between the groups (dorzolamide 37% versus brinzolamide 52%, P = 0.40). CONCLUSIONS: We concluded that the efficacy of brinzolamide 1% was equivalent to dorzolamide 1%; however, the safety of brinzolamide 1% was superior to dorzolamide 1% as adjunctive therapy to the combination with latanoprost and a beta-blocker.

Reliability of the first eye and second eye in frequency doubling technology perimetry.

PURPOSE: To compare the reliability of the perimetry results of the first eye and the second eye with frequency doubling technology (FDT). METHODS: The subjects were 328 residents who underwent the C-20-5 mode of FDT at a city in central Japan. FDT perimetry was always performed first in the right eye and then in the left eye without any time between tests. When more than 33% fixation loss or false-positive error was detected, the result was judged unreliable. RESULTS: Of the 328 subjects, the bilateral perimetry results were reliable in 255 subjects (77.7%), the unilateral results were reliable in 57 (17.4%), and there was not a reliable result in either eye in 16 (4.9%) subjects. Of the 57 subjects whose unilateral result was unreliable, the result of the second eye was unreliable in 50 (88%) subjects, and the result of the first eye was unreliable in 7 (12%). This difference in the reliability between the first eye and second eye was significant (P < 0.001). There were no differences in the age, sex, visual acuity, refractive error, test duration, or number of glaucoma suspects between the two groups whose unilateral result was unreliable in the first eye or the second eye. CONCLUSIONS: The FDT perimetry result of the second eye was less reliable than that of the first eye.

Comparison of annual cost between brand and generic ocular beta-adrenergic blockers.

We conducted a study of the annual cost of various ophthalmic products used in Japan for treating glaucoma including six of brands and generic ocular beta-adrenergic blockers (38 products). The total number of drops in one bottle of each solution was counted drop by drop. The cost per drop was calculated by dividing the government-controlled standard prices by the total number of drops in one bottle. The annual cost of ophthalmic solution was calculated by multiplying the cost per drop by the number of drops typically used per day. The total number of drops of the ophthalmic solutions in one bottle ranged from 108 to 168. The yearly cost of the beta-adrenergic blockers studied ranged widely, from yen 5392 to yen 27236. Differences in the total number of drops and the usage effect on the annual cost of ophthalmic solutions were found. The annual cost depended on not only the price of the products but also on the total number of drops in one bottle and the usage. Annual cost data may be helpful in selecting ophthalmic products for treating glaucoma in Japan.

Statistical evaluation of the diagnostic accuracy of methods used to determine the progression of visual field defects in glaucoma.

OBJECTIVE: To evaluate trend-type analyses to judge the progression of visual field damage (VFD) of glaucoma in terms of ratios of making judgments of progression and specificity, and to report a new method. DESIGN: Retrospective analysis of visual field (VF) results of actual glaucoma cases and those simulated by computer, and receiver operating characteristic curve analysis of performance of methods to judge the progression of VFD. PARTICIPANTS: One hundred five eyes of 105 open-angle glaucoma (OAG) patients with progressing VFD and 355 eyes of 355 clinically stable OAG patients for VF simulation from 4 university-based referral practices. METHODS: Methods using regression analysis of total deviation (TD), mean deviation (MD), mean TD of a sectored VF, and original scoring used in the Advanced Glaucoma Intervention Study (AGIS) were compared. A VF test was repeated twice in a short period on the 355 stable OAG eyes, and test-retest fluctuation, including variance at each test point and covariance between 2 test points, was calculated to simulate stable glaucomatous VF series by computer. The sensitivity of each method was calculated with 105 progressing VF series, and specificity was calculated with 10,000 simulated stable glaucomatous VF series. MAIN OUTCOME MEASURES: Sensitivity (ratios of making judgments of progression), specificity, and diagnostic power. RESULTS: The methods using the TD slope on one test location showed a sensitivity of 0.848 to 1.000, with a specificity of 0.105 to 0.721, and on 2 adjacent test locations showed a sensitivity of 0.848, with a specificity of 0.722. A significant negative MD slope with P<0.05 showed a sensitivity of 0.524, with a specificity of 0.945. The method using a sectored VF showed a sensitivity of 0.695, with a high specificity of 0.946. The AGIS method showed a sensitivity of 0.305 to 0.467, with a very high specificity of 0.999 to 1.000. The method using previously reported mathematically sectored VFs showed a sensitivity of 0.790, with a specificity of 0.900, and higher diagnostic power (1.69) than the others in this study population. CONCLUSIONS: Most of the methods using the TD slope were characterized by high sensitivity, the AGIS method had a very high specificity, and those using VF sectors had reasonable sensitivity and specificity.

Aqueous humor flow in normal human eyes treated with brimonidine and dorzolamide, alone and in combination.

OBJECTIVES: To measure the effectiveness of topical 0.2% brimonidine tartrate as a suppressor of aqueous humor flow in the human eye compared with the effectiveness of 2% dorzolamide hydrochloride, and to measure the additivity of the effects of the 2 drugs. DESIGN: A randomized, double-masked, placebo-controlled study was performed in 20 healthy human subjects. The topical drugs were instilled twice daily the day before and again in the morning on the day of the measurements. The rate of aqueous humor flow was measured from 8 AM to 4 PM by clearance of topically applied fluorescein using a fluorophotometer, after administration of doses of each drug singly and both drugs together. Intraocular pressure (IOP) was measured with applanation tonometry. RESULTS: Compared with placebo, brimonidine reduced the aqueous humor flow by a mean +/- SD of 28.2% +/- 18.0% (P<.001), dorzolamide by 19.3% +/- 22.0% (P =.007), and the combination of brimonidine and dorzolamide by 37.2% +/- 20.6% (P<.001). The combination of both drugs statistically significantly suppressed aqueous humor flow compared with dorzolamide alone (P<.001) and brimonidine alone (P =.04). The IOP was reduced by a mean +/- SD of 11.6% +/- 10.1% (P<.001) by brimonidine, 8.5% +/- 14.1% (P =.02) by dorzolamide, and 17.9% +/- 16.5% (P<.001) by the combination. The combination of drugs reduced IOP better than dorzolamide (P<.001), but not more than brimonidine (P =.06). CONCLUSIONS: The combination of brimonidine and dorzolamide caused a further reduction of aqueous humor flow compared with each drug applied alone. The IOP was further reduced by the combination compared with dorzolamide alone, but not compared with brimonidine alone.

Improvement in cognitive impairment after cataract surgery in elderly patients.

PURPOSE: To evaluate whether cognitive impairment improves in elderly patients who have cataract surgery with intraocular lens (IOL) implantation. SETTING: Kouki Hospital, Yamaguchi, Japan. METHODS: A prospective observational study evaluated patients' scores on the Revised Hasegawa Dementia Scale (HDS-R) and the HDS-R minus 1 item regarding immediate regeneration (ie, function of vision and memory). Twenty patients (6 men, 14 women) with cognitive impairment had cataract surgery in 1 eye between March 1996 and July 2001 at Kouki Hospital, Japan. The mean age of the patients was 81.8 years (range 61 to 90 years). Twenty patients (4 men, 16 women) with cognitive impairment who did not have cataract surgery were selected as a control. The mean age in the control group was 84.3 years (range 70 to 93 years). The HDS-R was administered twice between March 1996 and July 2001. RESULTS: The mean HDS-R scores in the cataract surgery group improved from 12.5 points +/- 5.3 (SD) preoperatively to 16.6 +/- 6.2 points postoperatively; the improvement was significant (t = -5.02; P<.0001). After cataract surgery, the grade of cognitive impairment improved in 12 patients (60%), was unchanged in 7 (35%), and was worse in 1 (5%). CONCLUSION: Cataract surgery improved cognitive impairment in elderly Japanese patients.

Daily cost of ophthalmic solutions used to treat allergic conjunctivitis in Japan.

PURPOSE: To estimate the daily cost of various ophthalmic solutions used in Japan for treating allergic conjunctivitis, including nine anti-allergic drugs and six anti-inflammatory drugs. METHODS: The drops contained in one bottle of each solution were counted. The cost per drop was calculated by dividing the government-controlled standard prices by the total number of drops in one bottle, and the daily cost of therapy was calculated by multiplying the cost per drop by the number of drops to be given per day. RESULTS: The total number of drops of the anti-allergic drugs in a bottle ranged from 108 to 169 and that of the anti-inflammatory drugs from 100 to 145. The information in the package insert for these solutions recommends application 2-4 times daily. The price of the antiallergic drugs studied ranged from $6.35 to $8.38 and that of the anti-inflammatory drugs studied from $2.02 to $5.20. The daily cost of the anti-allergic drugs studied varied considerably, from $0.26 to $0.57; for the anti-inflammatory drugs the range was from $0.12 to $0.20. Variations in the total number of drops per bottle and in the recommended dosage affect the daily cost of ophthalmic solutions. CONCLUSIONS: At current prices, the volume of a drop and the dosage had a greater effect on the daily cost than the price of a bottle. Daily cost data may be helpful in selecting ophthalmic products for treating allergic conjunctivitis in settings where the prices of a given drug are relatively uniform.

A comparative clinical study of latanoprost and isopropyl unoprostone in Japanese patients with primary open-angle glaucoma and ocular hypertension.

PURPOSE: To compare the efficacy and safety of latanoprost versus isopropyl unoprostone (unoprostone) in Japanese patients with primary open-angle glaucoma (POAG) or ocular hypertension (OH). METHODS: An 8-week, multicenter, randomized, comparative study was performed in 48 Japanese patients with POAG or OH. Four patients (two in each group) withdrew from the study, but their data were included in the safety assessment but not in the intraocular pressure (IOP) evaluation. The patients were randomly treated with latanoprost 0.005% once daily or unoprostone 0.12% twice daily for 8 weeks. IOP was measured at baseline and 2, 4, and 8 weeks after treatment. In addition, ocular and systemic adverse events were recorded. RESULTS: The baseline IOPs were similar between the latanoprost (n = 25) and unoprostone (n = 19) groups (24.3 +/- 2.4 mm Hg vs 23.3 +/- 2.1 mm Hg, respectively, = 0.18). The IOP reductions from baseline at 2, 4, and 8 weeks after treatment were 5.8 +/- 2.4, 6.6 +/- 2.5, and 6.7 +/- 2.0 mm Hg in the latanoprost group, and 3.8 +/- 2.0, 3.5 +/- 2.3, and 3.3 +/- 3.0 mm Hg in the unoprostone group, respectively. The IOP reduction in the latanoprost group at 8 weeks was larger than that in the unoprostone group ( < 0.001, analysis of covariance). Five adverse events were observed in 4 (15%) of 27 patients in the latanoprost group, and five adverse events were observed in 4 (20%) of 21 patients in the unoprostone group. There was no difference in the incidence of adverse events between groups ( = 0.71). CONCLUSION: Latanoprost produced a statistically greater reduction in IOP than unoprostone in Japanese patients with POAG or OH.

Additive effect of bunazosin on intraocular pressure when topically added to treatment with latanoprost in patients with glaucoma.

PURPOSE: To investigate whether an alpha-1 blocker, bunazosin, has an additive effect on lowering intraocular pressure (IOP) when topically added to latanoprost treatment in patients with glaucoma. METHODS: Bunazosin twice a day was added topically to the treatment for 12 patients with glaucoma who had been instilling latanoprost once a day for more than 1 month. IOP was measured and adverse events were checked 2, 4 and 8 weeks after the addition of bunazosin to their treatment. RESULTS: One of the 12 patients dropped out in the course of the study. Therefore, 11 patients were included for the analysis of IOP, and 12 for the analysis of adverse events. IOPs were decreased significantly (P=.008, Wilcoxon signed rank test) from 18.2+/-3.4 mm Hg to 16.6+/-3.5 mm Hg 8 weeks after the addition of bunazosin. Adverse events were seen in 5 of the 12 patients. CONCLUSION: Bunazosin has an additive effect on lowering IOP when topically added to latanoprost treatment in glaucoma patients.

A case of traumatic cyclodialysis followed by ultrasound biomicroscopy.

We report a case of persistent traumatic cyclodialysis treated by goniophotocoagulation and observed by ultrasound biomicroscopy (UBM) throughout the course. A 16 year-old male was struck in his right eye by a rocket firework. After the injury, hypotony continued for 4 months and he was referred to Hiroshima University Hospital. At that time, the best visual acuity in his right eye was 0.2 and the intraocular pressure was 6 mmHg. Three hundred and sixty degrees of cyclodialysis, partial peripheral anterior synechia, hypotony maculopathy and subretinal proliferative tissue were observed. Cyclodialysis was obvious by UBM. From 4 months after the injury goniophotocoagulation was performed six times in 2 months. Intraocular pressure recovered 6 months after the injury and reattachment of cyclodialysis and disappearance of the suprachoroidal space were confirmed by UBM. UBM was useful in observing cyclodialysis throughout the course.

The mechanisms by which latanoprost free acid inhibits human carbonic anhydrase I and II.

Latanoprost, a prostaglandin F2 alpha analogue, has been shown to be an effective ocular hypotensive agent when used alone on ocular hypertensive or open angle glaucoma patients. Carbonic anhydrase (CA) inhibitors are also used to reduce ocular hypertension by decreasing aqueous humor secretion, and are given in combination with prostaglandin F2 alpha analogue. It has been shown that prostaglandin F2 alpha, Minprostin F2 alpha, has been shown to increase the carbonic anhydrase (CA) activity and blood pressure. However, the effects of latanoprost on CA have not been clarified. Therefore, we studied the effects of latanoprost free acid on human carbonic anhydrase (HCA) I and II using the stopped flow method. Latanoprost free acid inhibited the hydration activity of HCA I or II by a noncompetitive mechanism. The inhibition constants (Ki) of latanoprost free acid for HCA I and II were 0.22 and 2.3 mM, respectively. Therefore, latanoprost free acid is a weak inhibitor of HCA I or II. AutoDock simulation of the latanoprost free acid-HCA I or II complex showed that the carboxylic moiety of latanoprost free acid, which is located at the end of the molecule, binds to the zinc ion of the active site by stretching of the chain of latanoprost free acid through the narrow and deep active site cavity of HCA I or II. In the active site cavity of HCA I or II, one side is hydrophilic and the other is hydrophobic. AutoDock simulation results clearly showed that latanoprost free acids lie down on the hydrophobic sides of the active site cavities in HCA I and II. The noncompetitive inhibition mechanism and the binding mode of latanoprost free acid indicate that the behavior of latanoprost free acid is very similar to that of simple anions.

Contact-based stiffness sensing of human eye.

Goldmann applanation tonometry is commonly used for measuring intraocular pressure (IOP) to diagnose glaucoma. However, the measured IOP by conventional applanation tonometry is valid only under the assumption that all subjects have the same structural eye stiffness. This paper challenges in vivo measurement of eye stiffness with a noninvasive approach and investigates individual differences of eye stiffness. Eye stiffness is defined by the applied force and displacement of the cornea. The displacement is detected based on captured images by a high resolution camera. The experimental results show that the measured stiffness nicely matches the analytical result that is derived from a simple spherical deformation model with an internal pressure. However, some subjects have different eye stiffness even with the same IOP. IOP with abnormal stiffness may be over/underestimated by conventional applanation tonometry. The proposed eye stiffness measurement can help detect the misestimated eye and it contributes to the early detection of glaucoma.

Retinal mean transit time in patients with primary open-angle glaucoma and normal-tension glaucoma.

PURPOSE: To compare the mean transit time (MTT) of retinal circulation in eyes with primary open-angle glaucoma (POAG) and eyes with normal-tension glaucoma (NTG) and examine the possible relationship between MTT and visual field damage, expressed as mean deviation (MD). METHODS: Video fluorescein angiography was performed in 40 patients with POAG or NTG. Dye curves for fluorescein passing through the retinal arteries and veins were used to calculate MTT in each patient with a computer-assisted technique based on an impulse-response analysis (MTT(IR)). RESULTS: We were able to analyse MTT(IR) in all 40 angiograms. Mean (SD) MTT(IR) was 5.0 (1.5) seconds in eyes with POAG and 4.7 (1.4) seconds in eyes with NTG. The difference was not statistically significant. There was a weak but significant correlation between the MD and MTT(IR) (MTT(IR) = 4.12-0.08*MD; r = -0.49, p = 0.0013). CONCLUSIONS: The results demonstrate that loss of neuronal tissue in glaucoma is combined with an effect on the retinal circulation and that the effect is similar in eyes with NTG and eyes with POAG.