Clinical Ophthalmology
`
`Open access Full Text article
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`O r i g i n a l re s e a rCh
`
`Travoprost with sofZia® preservative system
`lowered intraocular pressure of Japanese normal
`tension glaucoma with minimal side effects
`
`shiro Mizoue 1
`Tadashi nakano2
`nobuo Fuse3
`aiko iwase 4
`shun Matsumoto 5
`Keiji Yoshikawa6
`
`On behalf of the iOP
`Change study group 7
`1Department of Ophthalmology,
`ehime University graduate
`school of Medicine, ehime, Japan;
`2Department of Ophthalmology,
`Jikei University school of Medicine,
`Tokyo, Japan; 3Department of
`integrative genomics, Tohoku Medical
`Megabank Organization, Miyagi, Japan;
`4Tajimi iwase eye Clinic, gifu, Japan;
`5Department of Ophthalmology,
`Tokyo Teishin hospital, 6Yoshikawa
`eye Clinic, Tokyo, Japan; 7iOP
`Checked and assessed in normal
`tension glaucoma by exceptional
`glaucomatologists study group, Japan
`
`Correspondence: shiro Mizoue
`Department of Ophthalmology,
`ehime University graduate school
`of Medicine, shitsukawa Toon,
`ehime, 791-0295, Japan
`Tel +81 89 960 5361
`Fax +81 89 960 5364
`email mizoue@m.ehime-u.ac.jp
`
`submit your manuscript | www.dovepress.com
`Dovepress
`http://dx.doi.org/10.2147/OPTH.S57640
`
`Background: This study aimed to evaluate the effect of travoprost with sofZia® preservative
`system for lowering the intraocular pressure (IOP) of Japanese normal tension glaucoma (NTG)
`patients.
`Methods: In this prospective, multicenter, open-label study, Japanese NTG patients with
`baseline IOPs ,20 mmHg were enrolled after three consecutive time measurements taken at
`screening and baseline visits. Travoprost with sofZia® was instilled once daily. Lowering effect
`on IOP, conjunctival hyperemia, superficial punctate keratopathy, and adverse events were
`examined at week 4, 8, and 12 after drug instillation.
`Results: One-hundred and three of the 107 enrolled patients (baseline IOP =15.2±2.0 mmHg
`[mean ± standard deviation]) completed the study. The mean IOP value as well as percent reduc-
`tion was significantly reduced at each visit after travoprost with sofZia® initiation (P,0.0001).
`The conjunctival hyperemia score was 1 or less throughout the study, though it increased sig-
`nificantly over time. No significant change was observed in superficial punctate keratopathy.
`The cumulative incidence of side effects such as eyelash changes, eyelid pigmentation, and
`deepening of the upper lid was 47.6%, 27.2%, and 16.5%, respectively.
`Conclusion: Travoprost preserved with sofZia® effectively lowered the IOP of Japanese NTG
`patients. It was well tolerated with few discontinuations due to adverse events.
`Keywords: travoprost with sofZia® preservative system, normal tension glaucoma (NTG),
`prostaglandin analogue
`
`Introduction
`Travoprost is a prostaglandin (PG) F2α analogue which is known to lower intraocular
`pressure (IOP). Travoprost preserved with antiseptic benzalkonium chloride (BAC)
`(Travatan® 0.004%, Alcon Laboratories, Inc., Fort Worth, TX, USA) or sofZia®
` preservative system (Travatan Z® 0.004%, Alcon Laboratories, Inc.) have been pre-
`scribed for glaucoma patients, but currently only the latter is available in Japan.
`Travoprost with BAC has demonstrated a similar IOP-lowering effect as 0.005%
`latanoprost in a Phase III comparative clinical trial on patients with primary open-angle
`glaucoma or ocular hypertension.1 Travoprost preserved with sofZia® has a similar
`IOP-lowering effect as seen in travoprost preserved with BAC.2
`In Japan, the most common form of glaucoma is normal tension glaucoma (NTG),
`which accounts for about 90% of primary open-angle glaucoma.3 It also accounts for ∼33%
`of primary open angle glaucoma in the United States and European Union.4,5
`Lowering IOP is the only evidence-based therapy for glaucoma and a recom-
`mended treatment of NTG.6,7 PG-related eye drops, including travoprost with sofZia®,
`Exhibit 1025
`ARGENTUM
`
`347
`Clinical Ophthalmology 2014:8 347–354
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`License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further
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`remain the drugs of first choice for glaucoma management.
`However, in the past, few studies have been conducted on
`patients with NTG.8–10
`We studied the IOP-lowering effect of travoprost with
`sofZia® in Japanese patients with NTG with the baseline
`IOPs ,20 mmHg. To the best of our knowledge, this is the
`first report on the effect and safety of travoprost with sofZia®
`in a large number of NTG patients.
`
`Material and methods
`study design
`This prospective, multicenter, open-label study was conducted
`from September 2010 to August 2011 in accordance with the
`principles of the Declaration of Helsinki. Of the potentially
`eligible patients, the only ones enrolled in the study were those
`who signed an informed consent form after having been given an
`explanation of its contents and having been informed of expected
`treatment for study participants. The protocol was reviewed and
`approved by the Ethics Review Committee of Asano Clinic and
`was approved separately by the following institutions’ respective
`internal ethics review committees: Tohoku University Hospital,
`Juntendo University Urayasu Hospital, Jikei University School
`of Medicine, Nakano General Hospital, Fussa Hospital, Fukui
`Saiseikai Hospital, Nissei Hospital, and Minami-Matsuyama
`Hospital. This study was published on the University Hospital
`Medical Information Network Clinical Trials Registry (UMIN-
`CTR) (Registration ID: UMIN000007026).
`
`Patients
`Newly diagnosed NTG patients or patients with a prior
`diagnosis of NTG but currently untreated were recruited
`from 22 institutions across Japan (Table S1) as potential
`patients.
`Enrolled patients were 1) male or female at least 20 years
`of age, 2) had untreated IOPs (baseline IOPs ,20 mmHg)
`consistently confirmed by at least three consecutive
` measurements taken at the screening and baseline visits, and
`3) had glaucomatous optic disc damage and glaucomatous
`visual field defects.
`Patients were excluded from the study if they had one or
`more of the following conditions: 1) any anterior eye segment
`abnormality preventing reliable Goldmann applanation
`tonometry, 2) mean deviation of less than −15 dB by a
`Humphrey field analyzer, 3) complications due to chronic/
`recurrent uveitis, scleritis, or corneal herpes, 4) history of
`hypersensitivity to PG-related drugs, 5) ocular injury, intraoc-
`ular surgery, or ocular laser surgery within 3 months before
`the baseline examinations, and 6) use of a corticosteroid
`
`or any IOP-lowering drug other than travoprost during
`the study. Pregnant/breast-feeding women, patients with
` psychological problems, and those considered by the attend-
`ing ophthalmologist to be inappropriate study participants
`were also excluded. Dry eye patients were not excluded in
`this study.
`
`Procedures
`One drop of travoprost with sofZia® preservative system was
`instilled either bilaterally or unilaterally into the conjunctival
`sac at the discretion of the attending ophthalmologist once
`daily, between 8 pm and 10 pm for 12 weeks.
`IOP was measured in duplicate at 4, 8, and 12 weeks
`after the initiation of treatment with a Goldmann applana-
`tion tonometer by the same operator within 2 hours before or
`after the scheduled time. The mean values of IOPs in the eye
`having the higher IOP or the right eye (if the left and right
`eyes had the same IOP) were used for the analysis.
`The degrees of superficial punctate keratopathy (SPK) and
`conjunctival hyperemia were assessed by slit-lamp observa-
`tion at 4, 8, and 12 weeks after the initiation of treatment.
`SPK was graded 0 to 4 at each of five areas according to the
`corneal diagram of the National Eye Institute.11 Conjunctival
`hyperemia was scored according to four grades: 0, no vaso-
`dilatation; 1, vasodilation of mainly small blood vessels;
`2, vasodilation of both large and small blood vessels;
`3, marked vasodilation including both large and small blood
`vessels. The degrees of SPK and hyperemia were judged by
`each ophthalmologist using a prepared reference diagram.
`Eyelash changes, eyelid pigmentation, and deepening of
`the upper lid were assessed visually by a doctor on duty in each
`institution. Presence or absence of changes was recorded.
`Subjective symptoms such as ocular irritation, foreign
`body sensation, dryness, and itching were scored on a four-
`point scale: absent, few, moderate, and apparent. Few, moder-
`ate and apparent symptoms were counted as the cumulative
`incidence.
`Blood pressure (mmHg) and pulse rate (beats per minute
`[bpm]) were measured at the beginning and at the end of the
`study. Visual fields were measured before and after the end
`of the study, and mean deviation (MD) values were compared
`(Humphrey field analyzer SITA standard Program 30-2 or
`Program 24-2; Carl Zeiss Meditec, Inc., Dublin, CA, USA).
`
`statistical analysis
`All collected data from each institution were sent to
`Tajimi Iwase Eye Clinic in a manner that protected patient
`confidentiality.
`
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`iOP lowering effect of travoprost in nTg patients
`
`15.2±2.0
`
`*
`
`*
`
`*
`
`12.2±2.0
`
`12.2±2.0
`
`12.2±2.1
`
`Baseline
`
`4
`
`8
`
`12
`
`Week
`
`20
`
`15
`
`10
`
`0
`
`Intraocular pressure (mmHg)
`
`Figure 1 iOP before and after travoprost with sofZia® administration.
`Notes: iOP is presented as the mean ± sD. *P,0.0001 for significant change of
`iOP compared with baseline by repeated measures analysis of variance and multiple
`comparison using Tukey’s hsD test. sofZia® (Travatan® 0.004%, alcon laboratories,
`inc., Fort Worth, TX, Usa).
`Abbreviations: hsD, honestly significant difference; IOP, intraocular pressure;
`sD, standard deviation.
`
`Study eyes were divided into three groups (,14 mmHg,
`$14 mmHg and ,17 mmHg, and $17 mmHg) according to
`baseline IOP. The mean IOP reduction as well as IOP percent
`reductions in each group was decreased significantly at each
`test point (P,0.0001) (Figure 3).
`The mean hyperemia scores were increased significantly
`(P,0.0001) at each time point, but 93 patients (90.3%) had
`the score of 1 or below throughout the study.
`No significant differences in the mean SPK scores were
`observed in each time point (Table 1). Total SPK score of
`87 patients was 0 prior to the treatment. SPK were worsened
`among 12 patients (13.8%). Sixteen patients had an SPK
`score 1 or higher prior to the instillation. Decrease in SPK
`scores was observed after 12 weeks in 12 patients (75.0%).
`For one patient, the total SPK score was 9 initially but
`decreased to 0 after 12 weeks.
`The most common side effects were eyelash growth
`(49 patients, 47.6%), followed by increase in eyelid pig-
`mentation (28 patients, 27.2%) and deepening of the upper
`eyelid (17 patients, 16.5%).
`Cumulative incidence of subjective symptoms detected
`in 42 patients was 40.8% during 12 weeks. Ocular irrita-
`tion (26.2%) was the most frequent symptom, followed by
` itching (18.5%), foreign body sensation (17.5%), and dryness
`(4.9%). Ocular irritation and itching were noted throughout
`the observation period, while foreign body sensation and
`dryness were seen for 8 weeks (Figure 4).
`MD value of visual field between baseline (−4.61±4.95 dB)
`and the 12 weeks time point (−4.36±4.89 dB) was not
` significantly different (P=0.1069).
`
`An ophthalmologist not involved in the data collection
`process independently verified NTG diagnosis based on
`ocular fundus photographs and visual field tests of enrolled
`patients.
`Baseline IOP was defined as the mean of three IOP
`measurements taken before treatment at the screening and
`baseline visits. IOP reduction and percent reduction of IOP
`from baseline was assessed in patients who were followed-up
`and treated for at least 4 weeks between visits, and compli-
`ance of treatment was confirmed at each visit. The results
`were analyzed by repeated measures analysis of variance
`(ANOVA) and multiple comparison using Tukey’s HSD
`(honestly significant difference) test.
`Degree of SPK and conjunctival hyperemia were ana-
`lyzed employing the Wilcoxon signed rank test. Cumulative
`incidence of eyelash change, eyelid pigmentation, deepening
`of the upper lid, and subjective symptoms were expressed as
`a percentage of patients.
`The changes in blood pressure, pulse rate, and MD of the
`visual field before and after the study were analyzed using
`the paired t-test.
`The statistical analysis software used was JMP version
`9.0 (SAS, Cary, NC, USA). All tests were two-tailed with a
`significance level set at 5%.
`
`Results
`One-hundred and seven patients with a diagnosis of NTG
`were included in this study. Of the 107 patients, 103 patients
`(48 men and 55 women) with a mean age of 61.4±13.6 years
`(28–87 years) completed the study. Four patients discontin-
`ued the study: one (0.9%) was lost to follow-up, and three
`(2.8%) discontinued due to side effects. One of these three
`patients developed lacrimation, discharge, hyperemia, and
`a foreign body sensation immediately after instillation on
`day 1. Two patients developed hyperemia, lower lid swelling,
`and foreign body sensation at 1–2 months after instillation
`and wished to discontinue the study. The study compliance
`rate was 96.3%.
`Travoprost with sofZia® preservative system (baseline
`IOP =15.2±2.0 mmHg) significantly reduced IOP at each
`test point (P,0.0001) (Figure 1).
`A more than 20% IOP reduction from baseline was
`observed in about 50% of eyes at each test point. Reduc-
`tions of 10%–20% were observed in 35%–40% of patients,
`and reductions of less than 10% IOP were seen in only
`11%–12% of treated eyes. The average reduction rate of IOP
`was 19.4%–19.8% at each visit, and these percent reductions
`were statistically significant (P,0.0001) (Figure 2).
`
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`≥30%
`
`≥20%
`
`≥10%
`
`<10%
`
`Average (%)
`
`Average percentage reduction of IOP
`
`50%
`
`40%
`
`30%
`
`19.7%
`
`19.8%
`
`19.4%
`
`20%
`
`10%
`
`0%
`
`4
`
`8
`Week
`
`12
`
`100%
`
`80%
`
`60%
`
`40%
`
`20%
`
`0%
`
`Cumulative percentage reduction of IOP
`
`Figure 2 Percentage reduction of iOP with drug administration.
`Notes: iOP reduction rates are classified into four categories represented by each column:
` $10%,
` $20%,
` $30%,
`mean ± sD. Vertical axes: left and right axes represent cumulative and average percentage reduction of iOP, respectively.
`Abbreviations: iOP, intraocular pressure; sD, standard deviation.
`
` ,10%. Open circle (
`
`) represents the
`
`No signif icant differences in a systolic and dia-
`stolic blood pressure and pulse rate were observed in
`101/103 patients (systolic blood pressure: 130.2±15.0/
`128.0±17.0 mmHg, P=0.0835; diastolic blood pressure:
`79.7±10.6/78.6±11.3 mmHg, P=0.2994; pulse rate:
`71.9±10.5/72.0±10.6 bpm, P=0.9539).
`
`Discussion
`Travoprost with sofZia® preservative system significantly
`reduced IOP in Japanese NTG patients with minimal local
`side effects.
`
`Though PGs are the first remedy for glaucoma with high
`IOP, the effectiveness and safety has not adequately been
`studied in patients with NTG. Travoprost with sofZia® use
`has been reported in limited numbers of NTG patients, with a
`potent IOP lowering effect and minimal corneal damage.12,13
`We, therefore, expanded on these findings and conducted a
`study with a large number of Japanese NTG patients.
`In the present study, more than 100 patients were dosed
`with travoprost with sofZia®, and their IOPs were reduced
`significantly from baseline at each time point. A significant
`average percent reduction of IOP (20% or more) was also
`
`≥17 mmHg (n=27)
`≥14 mmHg and
`<17 mmHg (n=47)
`
`<14 mmHg (n=26)
`
`* *
`
`*
`
`*
`
`*
`
`*
`
`*
`
`* *
`
`20
`
`15
`
`10
`
`5
`
`Intraocular pressure (mmHg)
`
`Baseline
`
`4
`
`8
`
`12
`
`Week
`
`Figure 3 Change of iOP in three groups with drug administration.
`Notes: eyes were classified into three groups based on their baseline IOP:  $17 mmhg,  $14 mmhg and ,17 mmhg,  ,14 mmhg. *P,0.0001 for significant change
`of iOP compared with each baseline by repeated measures analysis of variance and multiple comparison using Tukey’s hsD test.
`Abbreviations: hsD, honestly significant difference; IOP, Intraocular pressure.
`
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`iOP lowering effect of travoprost in nTg patients
`
`Total sPK score
`superior
`nasal
`Temporal
`Central
`inferior
`hyperemia score
`
`Table 1 sPK and hyperemia scores
`12 week
`8 week
`Baseline
`4 week
`0.32±0.81
`0.40±0.86
`0.35±1.12
`0.30±0.70
`0.00±0.00
`0.00±0.00
`0.01±0.10
`0.00±0.00
`0.08±0.33
`0.09±0.32
`0.05±0.22
`0.06±0.31
`0.02±0.14
`0.05±0.22
`0.06±0.42
`0.01±0.10
`0.03±0.17
`0.02±0.14
`0.04±0.27
`0.02±0.20
`0.19±0.47†
`0.24±0.49†
`0.17±0.51†
`0.21±0.48†
`0.51±0.63*
`0.53±0.61*
`0.14±0.40
`0.54±0.61*
`Notes: scores are indicated as mean ± sD. *P,0.0001 for significant change of
`hyperemia score compared with baseline by Wilcoxon signed rank test. †P,0.01 for
`significant difference of SPK score at each time point compared with other corneal
`area by Wilcoxon signed rank test.
`Abbreviations: SD, standard deviation; SPK, superficial punctate keratopathy.
`
`seen in the majority of patients at each test point. Although
`the target IOP level in the treatment of NTG has yet to be
`established, a 20% IOP reduction from baseline is a reason-
`able target in Japan.7,14
`Approximately 10% of the patients did not reach a 10%
`IOP reduction rate from their baseline. Nonresponders to
`PGs account for approximately 20% of glaucoma patients
`with high IOP;15 therefore, the rate of “nonresponders” in the
`present study was fewer than in other studies. Eight patients
`were “late responders,” whose initial IOP-lowering rate was
`less than 10%, but their IOP decreased further at 2–3 months
`in this study. These results suggest that at least a 3-month
`observation period was needed to determine the effectiveness
`of travoprost with sofZia® and other PG-related eye drops.
`Significant reduction in IOP was observed in all three
`groups according to baseline IOP. In Japan, about 20% of
`NTG eyes have baseline IOPs of 14 mmHg or less. Even for
`those patients, travoprost with sofZia® was able to further
`
`reduce their IOPs. Therefore, it is a suitable option to reach
`the therapeutic goals in patients with NTG in Japan.
`In this study, SPK and conjunctival hyperemia, the most
`frequent side effects of PG instillation therapy, were scored
`using the National Eye Institute classification and reference
`pictures for the objective evaluation. Conjunctival hyperemia
`showed significant worsening after dosing. Hyperemia might
`affect patient adherence; however, the overall scores remained
`low throughout the study period. Hence no patient discontin-
`ued the study due to hyperemia, and the overall scores were
`even slightly lower than in a previous report.16 Therefore, we
`concluded that the conjunctival hyperemia observed in this
`study is not particularly remarkable and is consistent with
`those seen in other PG-related eye drops.17,18 One patient was
`discontinued due to allergic symptoms such as hyperemia and
`lacrimation on day 1. PGs are not suitable in rare cases,19 so
`assessing the patient’s medical history prior to the application
`of the drug is important.
`There was no significant increase in SPK scores in each
`area of the cornea, although baseline SPK score was signifi-
`cantly higher in the lower corneal area of dry eye patients.
`Some suggest travoprost with sofZia® is safest for the
`cornea;20–22 however, we could not directly compare it with
`travoprost preserved with BAC in NTG patients because the
`latter is not available in Japan. The result in this study sug-
`gests that travoprost with sofZia® is safe on the cornea.
`Compared with the previous reports on travoprost with
`sofZia®,23,24 the incidence of eyelash change, eyelid pigmen-
`tation, and deepening of the upper lid was not high. But we
`did not assess the results with photography, therefore the
`incidence could be underestimated. It would be ideal to have
`
`Ocular irritation
`
`Itching
`
`Foreign body sensation
`
`Dryness
`
`30
`
`25
`
`20
`
`15
`
`10
`
`5
`
`Cumulative incidence rate (%)
`
`4
`
`8
`Week
`
`12
`
`Figure 4 Cumulative incidence of subjective symptoms.
`Notes: The cumulative incidence of adverse events in this study was 40.8% (by week 12). The most frequently observed event was ocular irritation [: 26.2%, n=27], itching
`(: 18.5%, n=19), foreign body sensation (: 17.5%, n=18) and dryness (: 4.9%, n=5).
`
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`a third person evaluate these changes; however, this study
`was a clinical trial across Japan, therefore, it was difficult
`to take standardized photos using the same photographic
` instruments. The cumulative incidence of subjective symp-
`toms was similar to a rate in the previous report.25 The MD
`values of the visual field showed no significant change. The
`mean blood pressure and pulse rate also showed no signifi-
`cant change after treatment. Although adverse events were
`observed, we conclude that their frequency was not high,
`and they are clinically tolerable.
`
`Conclusion
`Our study indicates that travoprost with sofZia® preservative
`system has a significant IOP-lowering effect in Japanese
`patients with NTG and is well tolerated.
`
`Acknowledgments
`This study was conducted with funding and support from
`the Japan Association of Health Service and Alcon Japan
`Ltd. The authors thank Kozaburo Hayashi for reviewing
`the manuscript.
`
`Disclosure
`Dr Mizoue has received compensation for the manuscript
`from Alcon Japan Ltd, and lecture fees from Alcon Japan
`Ltd, Pfizer Japan Inc., MSD K K, NIDEK Co, Ltd, Senju
`Pharmaceutical Co, Ltd, Santen Pharmaceutical Co, Ltd,
`and Kaken Pharmaceutical Co, Ltd. Dr Nakano has received
`lecture fees from Alcon Japan Ltd, Santen Pharmaceutical
`Co, Ltd, Otsuka Pharmaceutical Co, Ltd, R-Tech Ueno
`Ltd, Senju Pharmaceutical Co, Ltd, Carl Zeiss Co, Ltd,
`Kaken Pharmaceutical Co, Ltd, MSD K K, and Pfizer
`Japan Inc., Dr Fuse has received lecture fees from Alcon
`Japan Ltd, Santen Pharmaceutical Co, Ltd, Pfizer Japan
`Inc., and MSD KK. Dr Iwase has received consultant fees
`from Topcon Corporation and fees for expert testimony
`from KOWA Pharmaceutical Co, Ltd, and lecture fees from
`Alcon Japan Ltd, Santen Pharmaceutical Co, Ltd, Carl
`Zeiss Co, Ltd, and Pfizer Japan Inc., Dr Matsumoto has
`received lecture fees from Alcon Japan Ltd, Santen Phar-
`maceutical Co, Ltd, and Kaken Pharmaceutical Co, Ltd.
`Dr Yoshikawa has received fees for expert testimony from
`Santen Pharmaceutical Co, Ltd, and lecture fees from Alcon
`Japan Ltd, Santen Pharmaceutical Co, Ltd, Pfizer Japan Inc.,
`Kaken Pharmaceutical Co, Ltd, Senju Pharmaceutical Co,
`Ltd, and MSD KK. The authors report no other conflicts
`of interest in this work.
`
`References
`
`1. Netland PA, Landry T, Sullivan EK, et al. Travoprost Study Group.
`Travoprost compared with latanoprost and timolol in patients with
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`Mizoue et al
`
`Supplementary material
`
`Table S1 iOP Checked and assessed in normal tension
`glaucoma by exceptional glaucomatologists (Change) study
`group
`
`Institution
`1. Tohoku University, Department of
`Ophthalmology, Miyagi, Japan
`2. Yaoeda eye Clinic, niigata, Japan
`3. hara eye hospital, Tochigi, Japan
`4. Juntendo University Urayasu hospital,
`Chiba, Japan
`5. The Jikei University school of Medicine
`Department of Ophthalmology, Tokyo, Japan
`6. Yoshikawa eye Clinic, Tokyo, Japan
`7. Ueno eye Clinic, Tokyo, Japan
`8. nakano general hospital, Tokyo, Japan
`9. Fussa hospital, Department of
`Ophthalmology, Tokyo, Japan
`10. nihonmatsu eye hospital, Tokyo, Japan
`11. Matsukura eye Clinic, Kanagawa, Japan
`12. nishikamakura Tanino eye Clinic,
`Kanagawa, Japan
`13. Fukui-ken saiseikai hospital, Department
`of Ophthalmology, Fukui, Japan
`14. Tajimi iwase eye Clinic, gifu, Japan
`15. Yamabayashi eye Clinic, aichi, Japan
`
`16. nissei hospital, Department of
`Ophthalmology, Osaka, Japan
`17. hirakata Yamagishi eye Clinic, Osaka, Japan
`18. Kozaki eye Clinic, Osaka, Japan
`19. Minami-Matsuyama hospital, Department
`of Ophthalmology, ehime, Japan
`20. Mizoguchi eye Clinic, nagasaki, Japan
`21. Ozaki eye Clinic, Miyazaki, Japan
`22. Unoki eye Clinic, Kagoshima, Japan
`Abbreviation: iOP, intraocular pressure.
`
`Researcher
`nobuo Fuse
`
`Kiyoshi Yaoeda
`Takeshi hara
`itaru Kimura
`
`Tadashi nakano
`
`Keiji Yoshikawa
`Tairo Kimura
`hirotaka suzumura
`Toyoaki Tsumura
`
`Mami nanno
`shuji Matsukura
`Tomihiko Tanino
`
`Koji nitta
`
`aiko iwase
`shigeki
`Yamabayashi
`reiko sugimoto
`
`Kazuya Yamagishi
`Jun Kozaki
`shiro Mizoue
`
`Takanori Mizoguchi
`Mineo Ozaki
`Kazuhiko Unoki
`
`Clinical Ophthalmology
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