Hidetoshi Tsukamoto

Hiroshima University, Hiroshima-shi, Hiroshima-ken, Japan

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Publications (43)66.45 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Biological & Pharmaceutical Bulletin 02/2010; 33(2):301-6. · 1.85 Impact Factor
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    ABSTRACT: 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.
    Biological & Pharmaceutical Bulletin 06/2008; 31(5):796-801. · 1.85 Impact Factor
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    ABSTRACT: 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.
    IEEE transactions on bio-medical engineering 03/2008; 55(2 Pt 1):739-45. · 2.15 Impact Factor
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    ABSTRACT: The clinical significance of a proper eye drop application technique was evaluated in Japanese glaucoma patients. Patients diagnosed with primary open-angle glaucoma having intraocular pressure (IOP) greater than 21 mmHg were treated with eye drops at home. In some patients, however, the topical treatment was ineffective. They returned to the hospital to receive surgical treatment. On admission, 56% of these patients had IOP greater than 21 mmHg. Patient instillation technique was evaluated based on the proximity of the eyedropper tip to the eyes, application position, eyelid closure, treatment (removal) of excess fluid, and nasolacrimal occlusion. In addition, pharmacists interviewed patients to determine the level of understanding of glaucoma, knowledge of prescribed drugs, home application technique, and sensation after application. Multivariate analysis revealed that the key factors influencing the control of IOP to less than 21 mmHg with topical medication were: application of drops in the center of the eye and removal of excessive fluid, in addition to gender and age. Proper topical application at home was dependent on the patient's understanding of the disease, knowledge of prescribed drugs, patient education on the use of drugs, the competence of the instructor, and knowledge of correct application technique. This study indicates that easily comprehensible patient education on the use of eye drops, the nature of glaucoma and the proper use of prescribed drugs is vital to improving the clinical efficacy of topical ophthalmic medication of glaucoma in adult patients.
    Pharmazie 02/2008; 63(1):81-5. · 0.96 Impact Factor
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    ABSTRACT: To investigate whether the aqueous levels of vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) are correlated to the vitreous levels of these substances and to the severity of macular oedema in branch retinal vein occlusion (BRVO). Aqueous and vitreous samples were obtained during cataract and vitreous surgery from 24 patients (24 eyes) with macular oedema in BRVO. The VEGF and IL-6 levels in aqueous humour, vitreous fluid, and plasma were determined by enzyme-linked immunosorbent assay. The degree of retinal ischaemia was evaluated in terms of the area of capillary nonperfusion using the Scion Image. The severity of macular oedema was evaluated using the OCT. The aqueous level of VEGF was significantly correlated with the vitreous level of VEGF (P<0.0001). Vitreous levels of VEGF and IL-6 were significantly correlated with the nonperfusion area of BRVO (P<0.0001, P=0.0061, respectively), as were the aqueous levels of VEGF and IL-6 (P<0.0001, P=0.0267, respectively). Furthermore, the vitreous levels of VEGF and IL-6 and the aqueous level of VEGF were significantly correlated with the severity of macular oedema of BRVO (P=0.0001, P=0.0331, P=0.0272, respectively). Our results suggest that the aqueous level of VEGF may reflect its vitreous level. Measurement of the aqueous level of VEGF may be clinically useful to indicate the severity of macular oedema with BRVO.
    Eye 02/2008; 22(1):42-8. · 1.82 Impact Factor
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    ABSTRACT: The contact tonometer is commonly used for measuring the internal eye pressure to diagnose glaucoma. However, the conventional eye pressure measurement is valid only under the assumption that all subjects have the same structural eye stiffness. This paper challenges to measure the contact area between the probe and the cornea in addition to the corneal deformation for considering the individual differences in the structural eye stiffness. Prior to the experiment, a spherical model of an eye is developed and the analytical eye stiffness is introduced. The experiment is conducted based on the contact method where a contact probe is pressed on an anesthetized cornea. The deformation of the cornea and the contact area are captured by cameras during the experiment. The experimental results show that the measured stiffness nicely matches the analytical solution based on the constructed model. However, some subjects have different relationships between the displacement and the contact area even with similar estimated eye pressures. This suggests that the structural eye stiffness should be considered for more precise diagnoses of glaucoma.
    Robotics and Automation, 2007 IEEE International Conference on; 05/2007
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    ABSTRACT: 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). 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)). 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). 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.
    Acta Ophthalmologica Scandinavica 03/2007; 85(1):67-72. · 1.85 Impact Factor
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    ABSTRACT: We investigated the differential protein expression patterns of retinal pigment epithelial (RPE) cells exposed to increased glucose concentrations. Cultured human RPE cells (ARPE-19) were exposed for 4 days with normal blood glucose concentration (5.5 mM D-glucose), followed by exposure to either normal (5.5 mM) or high (33 mM) concentrations of D-glucose for 48h. Protein extracts of glucose-treated RPE cells were then subjected to comparative proteome analysis based on 2-D gel electrophoresis. Protein spots were visualized by silver staining. The differentially expressed proteins were excised and digested in-gel with trypsin, then analysed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The expression levels of cathepsin B, glutathione peroxidase and heat shock protein 27 were increased, and that of protein disulfide isomerase decreased in high glucose treated RPE compared to normal glucose. The isoelectric point of copper/zinc-containing superoxide dismutase (Cu/Zn-SOD) shifted toward acidic region in response to high glucose. Cu/Zn-SOD activity in high glucose group was significantly lower than that in normal glucose group (P<0.05, Mann-Whitney U-test). Systematic survey of protein expression has revealed that RPE cells respond to acute, pathologically high glucose levels by the elevated expression of anti-oxidant and proteolytic enzymes.
    Experimental Eye Research 10/2006; 83(3):602-9. · 3.03 Impact Factor
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    ABSTRACT: For the diagnosis and treatment of glaucoma, a reliable and non-invasive measurement method of the internal eye pressure, i.e. the intraocular pressure (IOP), is desired. The IOP resists a deformation of the eye and thus non-contact tonometers, which deform the eye by a short air pulse, are suitable to estimate the IOP. By monitoring the reflection of an incident infrared light, the tonometer measures the time an applied air jet flattens part of the eye. The relationship between flattening time and IOP are provided by calibration. In our work, we used an additional high speed camera to capture the eye deformation directly and obtain more data during the pressure measurement. We show that the principle shape of the deformation can be understood by assuming simple non-linear material properties of the cornea in an eye model. Furthermore, we discuss which sources of error are still needed to be overcome to give a medical meaningful diagnosis for the examined eye by the data from the high speed camera
    Multisensor Fusion and Integration for Intelligent Systems, 2006 IEEE International Conference on; 10/2006
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    ABSTRACT: The internal eye pressure is an important index for judging whether an eye suffers from glaucoma or not. The conventional eye pressure measurement is valid only under the condition that all subjects have the same structural eye stiffness. This paper challenges stiffness sensing of the human eye by pressing it with a contact probe. The displacement of the eye is captured by a camera with high resolution. Experimental results show that the stiffness is roughly constant for each subject, while it differs by up to a factor of five between subjects. The method can detect subjects whose eye stiffness is smaller than average for further careful medical examination
    Robotics and Automation, 2006. ICRA 2006. Proceedings 2006 IEEE International Conference on; 06/2006
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    ABSTRACT: To investigate whether vascular endothelial growth factor (VEGF) or interleukin-6 (IL-6) contributes to the pathogenesis of macular edema in eyes with branch retinal vein occlusion (BRVO), the correlations between these factors were investigated. We studied 25 patients suffering from macular edema with BRVO and 14 patients with nonischemic ocular disease (control group). The degree of retinal ischemia was evaluated in terms of the area of capillary nonperfusion using Scion Images, and the severity of macular edema was examined using optical coherence tomography. Vitreous fluid samples were obtained at the time of vitreoretinal surgery, and VEGF and IL-6 levels in the vitreous fluid and plasma were determined by means of enzyme-linked immunosorbent assays. Vitreous fluid levels of VEGF and IL-6 were significantly elevated in patients with BRVO compared with control patients (P = 0.0011 and P < 0.0001, respectively). Also, the vitreous level of VEGF was significantly correlated with that of IL-6 (P = 0.0012), and vitreous levels of VEGF and IL-6 were correlated with the size of the BRVO nonperfusion area (P < 0.0001 and P = 0.0033, respectively). Furthermore, vitreous levels of VEGF and IL-6 were correlated with the severity of macular edema (P = 0.0008 and P = 0.0191, respectively) and the severity of macular edema of BRVO was significantly correlated with the size of the BRVO nonperfusion area (P=0.0044). The levels of VEGF and IL-6 are increased in patients with macular edema with BRVO and are significantly correlated with the size of the nonperfusion area and the severity of macular edema. Therefore, they may play a role in macular edema with BRVO.
    Albrecht von Graæes Archiv für Ophthalmologie 03/2006; 244(3):309-15. · 1.93 Impact Factor
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    ABSTRACT: The internal eye pressure is an important index for judging whether an eye suffers from glaucoma or not. The conventional eye pressure measurement is valid only under the condition that all subjects have the same structural eye stiffness. This paper challenges the practice of measuring the stiffness of a human eye by pressing the cornea with a contact probe. The displacement of the eye is captured by a camera with high resolution. Experimental results suggest that the measured eye stiffness nicely matches with the theoretical estimation. Based on the experimental results, the difference between the eye stiffness measured by the contact method and the non-contact method is discussed.
    Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 02/2006; 1:2312-5.
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    ABSTRACT: Non-contact tonometers are widely used to measure the internal eye pressure, i.e. the IntraOcular Pressure (IOP), which is an important parameter for the diagnosis and treatment of glaucoma. During the measurement, the eye is deformed by a short air pulse. Commonly the pressure dependent deformation is estimated from the time when the eye becomes flat, which is derived from the monitored reflection of an incident infrared light. We used a high speed camera to capture the complete motion of the eye directly and obtain more data during the pressure measurement. Assuming a simple eye model with non-linear material properties of the cornea, we extend our previous analysis of the motion of the eye, and obtain a similar principle shape of the eye deformation as observed in the experiments.
    Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 02/2006; 1:5428-31.
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    ABSTRACT: To compare the prevalence of glaucoma in adults with Down's syndrome (DS) to that in non-DS control adults. 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. 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). The prevalence of glaucoma in adult patients with DS was significantly higher than that in age-matched control subjects.
    Japanese Journal of Ophthalmology 01/2006; 50(3):274-6. · 1.27 Impact Factor
  • Hidetoshi Tsukamoto, Hidetaka Noma, Hiromu K Mishima
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    ABSTRACT: Without Abstract
    Japanese Journal of Ophthalmology 01/2006; 50(1):65-7. · 1.27 Impact Factor
  • Hidetoshi Tsukamoto, Satoshi Mukai, Aiko Iwase, Hiromu K Mishima
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    ABSTRACT: 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. 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. 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. 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.
    Japanese Journal of Ophthalmology 01/2006; 50(4):380-2. · 1.27 Impact Factor
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    ABSTRACT: 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. 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. 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. Substituting brinzolamide for dorzolamide maintained stable IOP with improvement in ocular comfort in patients with glaucoma.
    Journal of Ocular Pharmacology and Therapeutics 11/2005; 21(5):395-9. · 1.29 Impact Factor
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    ABSTRACT: 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). Retrospective case-control study. 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. 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). 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.
    American Journal of Ophthalmology 08/2005; 140(2):256-61. · 3.63 Impact Factor
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    ABSTRACT: 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.
    Yakugaku zasshi journal of the Pharmaceutical Society of Japan 06/2005; 125(5):463-7. · 0.46 Impact Factor
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    ABSTRACT: 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. 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. 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). 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.
    Journal of Ocular Pharmacology and Therapeutics 05/2005; 21(2):170-3. · 1.29 Impact Factor

Publication Stats

481 Citations
66.45 Total Impact Points

Institutions

  • 2001–2007
    • Hiroshima University
      • • Graduate School of Engineering
      • • Department of Ophthalmology and Visual Science
      • • Department of Ophthalmology
      Hiroshima-shi, Hiroshima-ken, Japan
  • 2006
    • Gifu Prefectural Tajimi Hospital
      Gihu, Gifu, Japan