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Purpose: To explore the effects of deep optic nerve head (ONH) structures on Bruch's membrane opening (BMO)-minimum rim width (MRW) and peripapillary retinal nerve fiber layer thickness (pRNFLT) in healthy eyes., Design: Prospective cross-sectional study., Methods: Two hundred five healthy eyes of 141 subjects (mean ± standard deviation of age and axial length (AXL): 46.9 ± 10.0 years and 24.79 ± 1.15 mm) were enrolled. Best fit multivariable linear mixed models identified factors associated with BMO-MRW and pRNFLT. Explanatory variables included age, gender, AXL, BMO and anterior scleral canal opening (ASCO) area and ovality, magnitude of BMO and ASCO shift, peripapillary choroidal thickness, lamina cribrosa (LC) parameters, prelaminar thickness, and peripapillary scleral (PPS) angle., Results: Thinner BMO-MRW was associated with older age, smaller ASCO/BMO offset magnitude, larger BMO area, thinner prelaminar thickness, deeper LC, and thinner pRNFLT (P = .011, <.001, .004, <.001, <.001, <.001 respectively). Thinner pRNFLT was associated with shorter AXL, smaller ASCO area, a more posteriorly bowed PPS, shallower LC and thinner BMO-MRW. (P = .030, .002, .035, .012, <.001 respectively) CONCLUSIONS: BMO-MRW and pRNFLT were influenced by several deep ONH structures such as BMO and ASCO position shift, BMO or ASCO area, prelaminar thickness, PPS bowing and LC depth in addition to patient characteristics such as age and AXL. The degree and/or direction of associations varied between deep ONH structures and BMO-MRW or pRNFLT. Despite both BMO-MRW and pRNFLT being surrogate parameters for RGC loss, a complex relationship with ONH deep-layer morphology was indicated., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

To characterize laser speckle flowgraphy (LSFG) pulse waveform parameters for ocular circulation evaluation, a multicenter, prospective, cross-sectional study was conducted in 111 eyes of 86 healthy Japanese individuals. Optic nerve head (ONH) tissue-area, vessel-area mean blur rate (MT and MV, respectively), and MT and MV pulse waveform parameters were obtained using LSFG and ONH structural parameters using planimetry. Multivariate linear mixed-effects modeled regression analysis identified factors contributing to MT- or MV-waveforms using age, gender, smoking history, body mass index, systolic and diastolic blood pressure, heart rate, intraocular pressure, axial length, disc, rim, and β-peripapillary atrophy areas, MT or MV, central retinal artery, and vein equivalents (CRAE and CRVE) as explanatory variables. MT- and MV-waveforms significantly correlated with one or more systemic factors, consistent with previous studies. Following confounding factor adjustment, MT-Skew significantly negatively correlated with β-PPA area (P = 0.026); MT- and MV-flow acceleration index positively correlated with CRAE, MT, and MV (P = 0.041-< 0.001), compatible with these parameters' observed correlations to systemic factors. Significantly negative correlations of the blowout score and acceleration time index to CRAE partly conflicted with their correlations to systemic factors, and other waveform parameters showed little correlation to ocular factors. Thus, Skew and flow acceleration index assisted the in vivo ocular circulation characterization.

Purpose: For research on circadian intraocular pressure (IOP), rebound tonometers are widely used with or without general anesthesia as a non-invasive approach to obtain IOP values. However, whether general anesthesia such as inhalation anesthesia with isoflurane affects the circadian rhythm of IOP and in turn IOP measurements is currently unclear. As such, data reporting IOP values obtained under general anesthesia should be interpreted with caution. The purpose of this study was to evaluate how general anesthesia with isoflurane inhalation affects the circadian rhythm of IOP., Methods: C57Bl/6J strain mice maintained using a 12h:12h light/dark cycle (lights on and off at ZT0 and ZT12, respectively) were used. IOPs were measured using a rebound tonometer (Icare TonoLab) before and 3, 5, 10, 15, and 30 min after initiating anesthesia in both light and dark phases (ZT 2-6 and ZT 14-18, respectively). Awake IOPs and IOPs at 3 and 5 min after anesthesia initiation were also obtained at ZT5, 8, 11, 14, 17, and 20 to assess IOP diurnal curves under gas anesthesia., Results: IOP values gradually decreased after anesthesia initiation in both light and dark phases (P < 0.001) and there was no interaction between light/dark phase and anesthesia time (P = 0.88). There was a slight, but not significant, reduction in IOP 3 min after initiating anesthesia (P = 0.23), and significant decreases in IOP occurred at subsequent timepoints (P ≤ 0.001). Both awake and anesthetized mice showed a robust IOP rhythm that reached a peak and trough in the dark and light phase, respectively. Awake IOP levels did not significantly differ from those for anesthetized mice at 3 min after anesthesia initiation at all time points (P ≥ 0.07)., Conclusions: Both awake and anesthetized mice demonstrated a robust circadian rhythm for IOP. Murine IOP showed similar gradual decreases under inhalation anesthesia with isoflurane in both the light and dark phases. IOPs measured using a rebound tonometer within 3 min of initiating isoflurane anesthesia were comparable to awake IOPs, and thus may be useful to monitor the circadian rhythm of IOP in mice., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: To evaluate the use of a 24-hr ocular dimensional profile recorded with a contact lens sensor (CLS) combined with a single tonometric intraocular pressure (IOP) reading to indicate the potential for exceeding the diagnostic threshold for normal tension glaucoma (NTG) in Japanese patients., Methods: Intraocular pressure (IOP) of untreated Japanese NTG patients was measured with tonometry every 3 hr from 9:00 to 24:00. The subsequent day a 24-hr CLS (SENSIMED Triggerfish, Sensimed AG, Lausanne, Switzerland) profile was recorded on the same eye. Patients initially diagnosed as NTG were reclassified as NTG when the measured IOP values were consistently <20 mmHg or as primary open-angle glaucoma (POAG) when IOP was ≥20 mmHg in at least 1 measurement. For each patient and each IOP time-point, IOP values were combined with information provided by the CLS profile ('classifier') to indicate the potential for exceeding the diagnostic threshold value. Statistical analyses were performed for each classifier., Results: A total of 65 patients, 28 males and 37 females (mean ages: 50.8 ± 14.6 years and 52.6 ± 10.2 years, respectively), were analysed. Following IOP diurnal measurement, five patients (7.7%) were reclassified as POAG. Two classifiers (15:00 CLS and 18:00 CLS) showed high sensitivity and negative predictive value (100%), identifying all the POAG patients., Conclusion: Contact lens sensor information can be used in conjunction with a single tonometric reading to determine patients' potential of having IOP levels exceeding the diagnostic threshold within a 24-hr period, without the need to perform a 24-hr tonometric curve. This would allow clinicians to identify POAG patients who may otherwise be eventually misclassified as NTG., (© 2020 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: To examine the efficacy and safety of current trabeculectomy with mitomycin C in Japan for glaucomatous eyes with low intraocular pressure (IOP)., Methods: Two hundred ninety-four eyes of 294 patients with IOP ≤21 mmHg before surgery were studied; all patients were participants in the Collaborative Bleb-related Infection Incidence and Treatment Study (CBIITS), a multicentre, prospective, cohort study conducted at 34 ophthalmological institutions throughout Japan. All eyes had an intraocular pressure ≤ 21 mmHg and had undergone trabeculectomy alone or phacotrabeculectomy. Two success criteria were used: Criterion A comprised 20% reduction of baseline IOP and Criterion B comprised 30% reduction of baseline IOP. The primary outcome was the success rate for each of these criteria., Results: The qualified success rates were 87.3% for Criterion A and 42.0% for Criterion B at 5 years. Mean IOP was significantly reduced, from 16.7 ± 2.7 to 11.6 ± 4.0 mmHg at 5 years after trabeculectomy (p < 0.0001); the number of anti-glaucoma medications significantly decreased from 2.7 ± 1.1 to 1.0 ± 1.2 (p < 0.0001) at 5 years after the surgery. Three or more trabeculectomies, and needling were related to increased risk of failure. Incidences of postoperative hyphema, infection, shallow anterior chamber and bleb leakage were 2.4%, 2.4%, 2.0% and 3.4%, respectively., Conclusions: This study showed that trabeculectomy with mitomycin C is an effective procedure with few surgical complications for reducing IOP in patients, even if preoperative IOP was within the normal range., (© 2019 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Purpose: In order to clarify the association between peripapillary vascular changes and disc hemorrhage (DH) occurrences over time, we analyzed the density of radial peripapillary capillary (RPC) and clinical parameters during follow-up periods in patients with normal-tension glaucoma (NTG)., Methods: Seventy-seven eyes of 77 NTG patients were subjected to analysis. We selected patients who had an initial optical coherence tomography angiography (OCTA) scan in 2015 and who had another OCTA scan in 2018 with both OCTA scans showing good-quality images. We investigated the relationships between DH occurrence and each of the following parameters: RPC density, circumpapillary retinal nerve fiber layer (cpRNFL) thickness slope and total deviation (TD) slope., Results: In the period between the initial and final OCTA, we categorized the patients into 53 sides with DH (DH group) and 101 sides without DH (non-DH group). The ΔRPC density of sides with DH was significantly greater than that of sides without DH (DH, - 4.42 ± 6.43%; without DH, - 2.48 ± 5.29%; p = 0.0469). The cpRNFL thickness slope of sides with DH was significantly faster than that of sides without DH (DH, - 2.85 ± 3.17; without DH, - 0.74 ± 2.46 μm/y; p < 0.0001). The TD slope of sides with DH was significantly faster than that of sides without DH (DH, - 0.50 ± 0.77; without DH, - 0.22 ± 0.53 dB/y; p = 0.0163). As DH occurrence increased, the RPC density significantly decreased (r = -0.255, p = 0.0014). Stepwise multiple regression analysis to identify factors influencing RPC changes showed that frequency of DH (β = - 0.224, p = 0.008) and central corneal thickness (β = - 0.220, p = 0.009) were significantly associated with RPC changes., Conclusions: DH occurrence may prompt the structural and vascular deterioration of NTG.

Purpose: To investigate the effect of trabeculectomy on the waveform changes of laser speckle flowgraphy (LSFG) in the optic nerve head (ONH) in patients with glaucoma., Methods: Forty-eight eyes of 48 patients with open angle glaucoma were included in this prospective study. LSFG was performed before and 1, 3, and 6 months after trabeculectomy. Longitudinal changes in average mean blur rate (MBR), blow out score (BOS), resistivity index (RI), falling rate, skew, acceleration time index, and blow out time in the tissue area of the ONH were analyzed by using mixed-effects models., Results: Intraocular pressure (IOP) decreased and ocular perfusion pressure increased significantly at each postoperative time point (P < 0.001, each). BOS increased (P < 0.001, each) and RI decreased (P < 0.001, each) significantly at each postoperative time point, although average MBR and other waveform parameters did not change significantly. Multivariate analyses revealed that younger age (coefficients = -0.13 and 0.0014, P = 0.006 and 0.03 for BOS change and RI change, respectively), worse baseline mean deviation of visual fields (coefficients = -0.18 and 0.0026, P = 0.009 and 0.005), larger IOP reduction (coefficients = -0.29 and 0.0037, P < 0.001, each), and larger pulse rate increase (coefficients = 0.17 and -0.0024, P < 0.001, each) are significantly associated with postoperative BOS increase and RI decrease., Conclusions: Given that postoperative BOS increased and RI decreased with the average MBR remaining unchanged, IOP reduction by trabeculectomy may contribute to stable blood flow throughout the duration of the heartbeat in the tissue area of the ONH.

Purpose: Intraocular pressure (IOP) fluctuates with a robust circadian rhythm, which is synchronized to organismal rhythmicity through the master circadian clock located in the suprachiasmatic nuclei. The mechanisms maintaining circadian synchrony between the suprachiasmatic nuclei and IOP rhythms are presently unknown. The purpose of this study was to evaluate the necessity and sufficiency of adrenal and glucocorticoid function for the entrainment of iris-ciliary body (iris-CB) and IOP circadian rhythms in mice., Methods: Iris-CB complexes were dissected from C57Bl/6J mice that were kept in 12-hour light/dark cycles at 3-hour intervals, and their core clock gene (Per1, Per2, and Bmal1) and glucocorticoid receptor mRNA expression were quantified. Iris-CB complexes from period2::luciferase mice were dissected and cultured to measure in vitro rhythmicity. To determine the phase-shifting effect of glucocorticoids on the iris-CB, dexamethasone or vehicle was added to the cultured tissues at defined circadian phases. The diurnal IOP rhythms of adrenalectomized or sham-operated mice under the 12-hour light/dark cycles were also measured., Results: In iris-CB complexes, glucocorticoid receptor mRNA expression remained stable throughout the day, whereas the mRNA of core clock genes showed a robust circadian rhythmicity. Dexamethasone significantly induced phase-delays when administered between circadian time 8 (CT8) to CT12 and phase-advance when given between CT16 to CT20. Adrenalectomy abolished circadian IOP rhythmicity, particularly diminishing nocturnal IOP elevation compared with sham-operated mice., Conclusions: Glucocorticoids are sufficient for phase shifting the circadian clock in iris-CB. Intact adrenal function is required for manifest circadian rhythms of IOP in mice. Taken together, these data are consistent with the hypothesis that glucocorticoids mediate circadian entrainment of IOP to the master circadian oscillator.

An objective method to predict individual visual field progression will contribute to realise personalised medication. The purpose of this study was to establish a predictive formula for glaucomatous visual field progression in patients with Primary open-angle glaucoma, mainly including normal tension glaucoma. This study was a large-scale, longitudinal and retrospective study including 498 eyes of 312 patients visiting from June 2009 to May 2015. In this analysis, 191 eyes of 191 patients meeting all eligible criteria were used. A predictive formula to calculate the rate of glaucomatous visual field progression (mean deviation slope) was obtained through multivariate linear regression analysis by adopting "Angle of Retinal Nerve Fibre Layer Defect" at the baseline, "Vertical Cup-Disc ratio" at the baseline, "Presence or absence of Disc Haemorrhage" during the follow-up period, and "Mean IOP change (%)" during the follow-up period as predictors. Coefficient of determination of the formula was 0.20. The discriminative ability of the formula was evaluated as moderate performance using receiver operating characteristic analysis, and the area under the curve was approximately 0.75 at all cut-off values. Internal validity was confirmed by bootstrapping. The predictive formula established by this type of approach might be useful for personalised medication.

Purpose: Intraocular pressure (IOP) is known to have a strong circadian rhythm, yet how light/dark cycles entrain this rhythm is unknown. The purpose of this study was to assess whether, like the retina, the mammalian ciliary body and IOP clocks have an intrinsic ability to entrain to light/dark cycles., Methods: Iris-ciliary body complexes were obtained from period2:luciferase (PER2::LUC) mice and cultured to measure bioluminescence rhythmicity. Pairs of the iris-ciliary body complex were exposed to antiphasic 9:15 h light/dark cycle in vitro. After 4 days of exposure to light/dark cycles, bioluminescence was recorded to establish their circadian phases. In addition, pairs of the iris-ciliary body complex co-cultured with the retinas or corneas of wild-type mice were also investigated. The IOP circadian changes of free-running Opn4-/-;rd1/rd1 mice whose behavior was antiphasic to wild-type were measured by a rebound tonometry, and compared with wild-type mice. Opn3, Opn4, and Opn5 mRNA expression in the iris-ciliary body were analyzed using RT-PCR., Results: The iris/ciliary body complex expressed Opn3, Opn4, and Opn5 mRNA; however, unlike in retina and cornea, neither the iris-CB complex nor the co-cultured complex was directly entrained by light-dark cycle in vitro. The diurnal IOP change of Opn4-/-;rd1/rd1 mice showed an antiphasic pattern to wild-type mice and their rhythms followed the whole-animal behavioral rhythm., Conclusions: Despite expressing mRNA for several non-visual opsins, circadian rhythms of the iris-ciliary body complex of mice do not entrain directly to light-dark cycles ex vivo. Unlike retina, the iris/ciliary body clocks of blind mice remain synchronized to the organismal behavioral rhythm rather than local light-dark cycles. These results suggest that IOP rhythm entrainment is mediated by a systemic rather than local signal in mice.

Purpose: To investigate whether the elimination of β1- and β2-adrenergic receptors alters the diurnal intraocular pressure (IOP) rhythm in mice., Materials and Methods: β1-/β2-adrenergic receptor double-knockout and C57BL/6J mice were anesthetized intraperitoneally, with their IOPs measured via microneedle method. After entrainment to a 12-h light-dark (LD) cycle (light phase 6:00-18:00), IOPs were measured every 3 h from 9:00 to 24:00 (group 1, β1-/β2-adrenergic receptor double-knockout mice, n = 11; C57BL/6J, n = 15). The IOP measurements at 15:00 and 24:00 under a 12-h LD cycle and in the constant darkness (1 day and 8 days after exposure to darkness, respectively) were performed in another group of β1-/β2-adrenergic receptor double-knockout mice (group 2, n = 12). IOP variance throughout the day and mean IOP differences among time points were evaluated using a linear mixed model., Results: β1-/β2-adrenergic receptor double-knockout and C57BL/6J mice showed biphasic IOP curves, low during the light phase and high during the dark phase; the fluctuation was significant (P < 0.001). The peak IOP (18.7 ± 1.4 mmHg) occurred at 24:00 and the trough IOP (13.5 ± 1.5 mmHg) occurred at 15:00 in β1-/β2-adrenergic receptor double-knockout mice group. IOP curves of β1-/β2-adrenergic receptor double-knockout and C57BL/6J were nearly parallel, and the IOPs of β1-/β2-adrenergic receptor double-knockout mice were significantly higher than those of C57BL/6J mice (P < 0.001). Under constant dark (DD) conditions, IOP at 24:00 (18.1 ± 1.5 mmHg) was significantly higher than that at 15:00 (13.3 ± 1.2 mmHg) (P < 0.001). The transition from the LD cycle to DD environment produced no significant change in IOP (P = 0.728)., Conclusions: Elimination of both β1- and β2-adrenergic receptors did not disturb the biphasic diurnal IOP rhythm in mice.

Purpose: To investigate the incidence of and factors associated with persistent hypotony after trabeculectomy with mitomycin C in the Collaborative Bleb-Related Infection Incidence and Treatment Study (CBIITS), a 5-year prospective multicenter study., Methods: A total of 955 eyes of 955 patients who underwent trabeculectomy with mitomycin C were studied. Surgical failure was defined as insufficient intraocular pressure (IOP) reduction (IOP > 21 mmHg or <20 % IOP reduction, or further glaucoma surgeries), loss of light perception, or persistent hypotony (IOP ≤ 5 mmHg persisting for >6 months). Factors associated with persistent hypotony in eyes with sufficient IOP reduction were determined by survival analysis and logistic regression analysis., Results: The cumulative probabilities of surgical success and persistent hypotony at 5 years were 62.0 ± 1.7 % (±standard error) and 7.7 ± 0.9 %, respectively. In 685 eyes with sufficient IOP reduction, preoperative IOP (mmHg), limbus-based conjunctival flap, or choroidal detachment that occurred within 6 months of the surgery were significant risk factors for persistent hypotony [Cox proportional hazards regression model: hazard ratio, 0.95, 2.27, 3.24; 95 % confidence interval (CI), 0.91-0.98, 1.21-4.23, 1.51-6.95; P = 0.005, 0.01, 0.003, respectively]. Bleb infection and final visual acuity (logarithm of the minimal angle of resolution) were significantly associated with persistent hypotony (logistic regression: odds ratio, 8.74, 1.37; 95 % CI, 1.89-40.4, 1.03-1.82; P = 0.006, 0.029, respectively)., Conclusions: In the CBIITS, eyes with successful IOP reduction, a limbus-based conjunctival flap, lower preoperative IOP, and choroidal detachment that occurred within 6 months of the surgery were identified as risk factors for persistent hypotony.

Purpose: To evaluate the efficacy and safety of trabeculectomy for patients with glaucoma who were enrolled in the Collaborative Bleb-related Infection Incidence and Treatment Study (CBIITS)., Design: Multicenter, prospective, cohort study., Participants: A total of 829 eyes in 829 patients with glaucoma who had undergone trabeculectomy alone or trabeculectomy combined with phacoemulsification at 34 clinical centers were examined in this study., Main Outcome Measures: Intraocular pressures (IOPs, in millimeters of mercury), risk factors for surgical failure, and surgical complications., Methods: The enrollment period was 2 years, and follow-up was conducted every 6 months for up to 5 years. Outcomes were measured at 6-month intervals. Four levels of success were defined by achievement of the following IOP: (A) 4

Purpose: To evaluate grid-wise analyses of macular inner retinal layer thicknesses and effect of compensation of disc-fovea inclination for diagnosing early-stage glaucoma., Methods: Spectral-domain optical coherence tomography measurements over a 6.0 × 6.0-mm macular area were prospectively obtained in 104 eyes of 104 patients with early-stage glaucoma with a mean deviation of -1.8 ± 1.9 dB and 104 eyes of 104 age- and refraction-matched normal subjects. Macular retinal nerve fiber layer (mRNFL), ganglion cell-inner plexiform layer (GCIPL) combined, and ganglion cell complex (GCC) thickness of the entire area and each subdivided macular grid were determined to compare diagnostic capability for glaucoma using receiver operating characteristic curves and various normal cutoff values for each layer thickness and number of grids flagged as abnormal. Diagnostic capability was then compared with that of circumpapillary RNFL (cpRNFL) measurements. Effects of compensation of inclination of disc-fovea line by reconfiguration of the macular grid were also studied., Results: Macular inner retinal layer analyses using 8 × 8 grids generally yielded higher diagnostic capability. Only the 8 × 8 grid GCC analyses using the various normal cutoff values yielded a sensitivity ≥ 0.90 with specificity ≥ 0.95 under several conditions in discriminating the glaucoma eyes. In glaucoma and normal eyes with both reliable cpRNFL and macular measurements, the best sensitivity/specificity were 0.98/0.95 for the 8 × 8 grid-mRNFL analysis and 0.93/0.96 for the 8 × 8 grid GCC analysis using various normal cutoff values, which were better than that (0.78/0.95) for clock-hour cpRNFL analysis (P = 0.001). Compensation of the disc-fovea inclination did not improve the diagnostic capability., Conclusions: Grid-wise analysis of macular GCC--especially using 8 × 8 grids and normative data-based cutoff values--was very useful for diagnosing early-stage glaucoma, though compensation of the disc-fovea inclination had little effect.

Aim: To examine whether intraocular pressure (IOP) reduction by latanoprost correlates with single nucleotide polymorphisms (SNPs) of the prostaglandin F2α (FP) receptor gene in patients with glaucoma and ocular hypertension (OH)., Methods: The genotype of nine SNPs in the FP receptor gene was determined by direct DNA sequencing, or other techniques, in 82 patients with glaucoma or OH who were treated with latanoprost monotherapy in one eye. The IOP reduction was evaluated by the percent IOP reduction (%ΔIOP), estimated by subtracting IOP fluctuations in the untreated fellow eye. Subjects were classified by %ΔIOP into low responders (%ΔIOP<10%) and others (%ΔIOP ≥10%). The correlation between %ΔIOP and SNPs in the FP receptor gene was analysed., Results: Multiple regression analysis demonstrated that the rs12093097 was the only significant factor that correlated with %ΔIOP (p=0.039). Among estimated haplotypes, one haplotype that contained the minor allele only in rs3753380, was significantly correlated with low responders even after correction for multiple test (permutation test, p=0.037)., Conclusions: An association was found between SNPs of the FP receptor gene and the response to latanoprost in patients with glaucoma or OH. The FP receptor genetic polymorphism may influence the degree of IOP reduction by latanoprost in these patients.

Purpose: A 3-year prospective study was performed to evaluate treatment outcomes following selective laser trabeculoplasty (SLT) used as initial treatment for normal tension glaucoma (NTG)., Subjects and Methods: SLT was performed as initial treatment in 42 NTG patients (42 eyes). Thirty-seven of the patients were untreated and 5 patients had discontinued antiglaucoma medications. Two patients were excluded because they did not visit our clinic during the study period. The study was conducted on the remaining subjects (40 eyes of 40 patients)., Results: The intraocular pressure (IOP) was 15.8 +/- 1.8 mmHg before SLT, 13.2 1.9 mmHg after one year, 13.5 +/- 1.9 mmHg after two years, and 13.5 +/- 1.9 mmHg after three years. The IOP after SLT was significantly lower than that before SLT. One month after SLT, the outflow pressure was improved at least 20% (deltaOP) in 92.5% of the patients. The success rate for the effect of IOP reduction at three years after SLT was 40.0% by Kaplan-Meier survival analysis. 27.5% of the patients who had two consecutive deltaOP less than 20%, 25.0% of the patients who had begun antiglaucoma ophthalmic solution, and 15.0% of the patients who had undergone repeated SLT were judged to have reached the endpoint. Kaplan-Meier survival analysis revealed that the success rate for the visual field at three years after SLT was 82.4% (the visual field loss progression was judged to have reached its endpoint when a significant sensitivity loss was first detected in two consecutive points of the same adjacent test points of at least 3 points in the Glaucoma Progressive Analysis for the Humphrey Visual Field Analyzer). Complications included conjunctival hyperemia (52.5%), eye discomfort (12.5%), visual disturbance (blurry vision and photophobia) (10.0%), and eye pain (5.0%). These complications resolved within a few days, and there were no severe complications such as increased IOP or iritis., Conclusion: Our results suggest that SLT is an effective initial treatment for NTG.

Purpose: To differentiate superior segmental optic hypoplasia (SSOH) from normal-tension glaucoma (NTG) with inferior visual field defects only., Methods: Eighteen eyes with SSOH (SSOH group) and 19 eyes with NTG (NTG group) were examined by optical coherence tomography (OCT), Heidelberg retina tomography (Heidelberg Retinal Tomograph II, HRT II) and standard automated perimetry., Results: Retinal nerve fiber layer thickness (RNFLT) based on OCT measurements was significantly reduced (thinner) in the superior to superonasal sectors and significantly greater (thicker) in the inferotemporal sector in the SSOH group than in the NTG group. The cup was significantly smaller and the rim significantly larger in the superotemporal and temporal sectors in the SSOH group than in the NTG group based on HRT II measurements. The greatest area under the receiver operating characteristic curve for discrimination of SSOH from NTG by OCT and HRT II was for the RNFLT ratio of 1 + 2 o'clock/10 + 11 o'clock (0.985) and for the ratio of the superonasal to superotemporal sector of rim to disc area ratio and cup to disc area ratio (0.955), respectively. The frequent location of the inferior visual field defects corresponded to the difference in structural changes in both groups., Conclusions: Comparison of the superonasal to superotemporal sectors by OCT and HRT II were useful in differentiating SSOH from NTG with only inferior visual field defects.

Purpose: To compare the drug efficacy of four prostaglandin analogues (PGAs) by bilateral treatment in normal subjects., Methods: Three consecutive studies comparing latanoprost to three other PGAs (travoprost, tafluprost and bimatoprost) were performed in 24 healthy subjects. Each study was separated by a washout period of over 6 weeks. In each study, two drugs were randomly assigned to one eye of each subject. Study subjects instilled the assigned medication at 9:00 p.m. every day for 2 weeks. The same masked investigator measured intraocular pressure (IOP) at 9:00 a.m., 1:00 p.m. and 5:00 p.m. at baseline and repeated measurements on days 7 and 14. The differences in IOP reduction were compared between the drugs., Results: Mean diurnal IOP reduction with latanoprost on days 7 and 14 was similar to that with travoprost and tafluprost, but was significantly lower than that with bimatoprost. The association of the mean diurnal IOP reduction between latanoprost and bimatoprost on day 14 (r (2) = 0.25) was weak, in remarkable contrast to the strong association between latanoprost and travoprost (r (2) = 0.81) and between latanoprost and tafluprost (0.82)., Conclusions: The short-term bilateral treatment revealed a different IOP-lowering efficacy of bimatoprost compared to other PGAs in healthy subjects.

Purpose: To examine the effects of multiple intraocular pressure (IOP) measurements on the correlation of response to glaucoma medication between fellow eyes., Methods: Latanoprost was applied to the first eye and then to both eyes of 16 patients with either primary open-angle glaucoma or ocular hypertension. IOP measurements were performed twice on different days for each of three periods: at baseline, during treatment of the first eye only and for both eyes. IOP decreases in the first and second eyes were evaluated with ∆IOP 1 (=IOP at baseline - IOP after treatment) and ∆IOP 2 (=∆IOP 1 - IOP fluctuation of the contralateral eye). The correlation of IOP decreases between the fellow eyes was analyzed by linear regression analysis using the Pearson correlation coefficient, r., Results: No significant correlations of ∆IOP1 between fellow eyes were found regardless of the number of IOP measurements. ∆IOP2 was significantly correlated between fellow eyes using two post-treatment IOP measurements, but not with a single post-treatment IOP., Conclusions: Using multiple post-treatment IOP measurements may improve the prediction of a fellow eye's response to glaucoma medication in one-eye trials.

Purpose: To evaluate the effect on intraocular pressure (IOP) of increased corneal thickness after Descemet's stripping automated endothelial keratoplasty (DSAEK) and of non-Descemet's stripping automated endothelial keratoplasty (nDSAEK) as measured by four different techniques., Methods: Twenty-four eyes (22 patients; mean age, 74.0 years) with successful DSAEK (11 eyes) or nDSAEK (13 eyes) treatment at least 3 months prior to testing were enrolled. IOP was measured with Goldmann applanation tonometry (GAT), dynamic contour tonometry (DCT), pneumatonometry, and Tono-Pen XL (Tonopen). Central corneal thickness (CCT) was measured by ultrasonic pachymetry. These data were used for statistical analysis., Results: Mean IOP measured by GAT, DCT, pneumatonometry, and Tonopen was 14.4, 13.9, 11.2, and 13.2 mmHg, respectively, in the DSAEK group; and 15.0, 14.4, 12.5, and 14.4 mmHg, respectively, in the nDSAEK group. Correlations between IOP and CCT were not statistically significant in either group. Pressure measured by pneumatonometry was significantly and consistently lower than that obtained by the other three methods., Conclusion: For both DSAEK and nDSAEK, IOP readings by the four tonometers seem to be unrelated to artificially thickened corneas.

Purpose: To evaluate the relationship between genetic polymorphisms of the adrenergic receptor (ADR) and diurnal intraocular pressure (IOP) in Japanese normal-tension glaucoma (NTG) patients., Design: Prospective, comparative case series., Participants: Ninety-two untreated NTG patients., Methods: The IOP of both eyes was measured at 3-hour intervals from 0600 to 2400 hours over 2 consecutive days. We used IOP data from the eye with the greater visual field defect for statistical analysis. The mean IOP over 2 days was used for each time point. Genetic polymorphisms in α1A-, α2A-, α2B-, α2C-, β1-, β2-, and β3-ADR were determined mainly by direct DNA sequencing. The relationship between IOP and genetic polymorphisms was analyzed., Main Outcome Measures: The IOP and genotypes of genetic polymorphisms., Results: Diurnal mean IOP of the subjects was 14.8 ± 2.1 mmHg (mean value ± standard deviation). For Del 301-303 in α2B-ADR, insertion/insertion (I/I) had a significantly higher diurnal mean IOP (P = 0.017), peak IOP (P = 0.038), and trough IOP (P = 0.046) than deletion (D) carriers. For Del 322-325 in α2C-ADR, I/I had a significantly lower diurnal mean IOP (P = 0.037) and peak IOP (P = 0.029) than D carriers. For S49G (A/G) in β1-ADR, A/A had a significantly higher diurnal mean IOP (P = 0.023), peak IOP (P = 0.019), and trough IOP (P = 0.014) than G carriers. For these 3 polymorphisms, repeated measures analysis of variance showed that the major homozygotes and minor carriers had parallel diurnal IOP curves, but significantly different diurnal IOP levels., Conclusions: Polymorphisms of the ADR gene may alter the untreated IOP level of patients with NTG., (Copyright © 2010 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To compare the correlation of the fellow-eye's intraocular pressure (IOP) response in one-eye trials performed separately for each eye with that of bilateral treatment in normal subjects., Methods: A one-eye trial with topical latanoprost applied once daily for 7 days was carried out in the right eye and then in the left eye of 41 normal subjects. Bilateral treatment was performed in a different set of 41 normal subjects. IOPs were measured at 3 time points on day 0 and on day 7., Results: Latanoprost significantly reduced IOP of treated eyes in one-eye trials (2.8+/-1.6 and 2.7+/-1.6 mm Hg in the first and second trial, respectively) and in bilateral treatments (2.8+/-1.3 and 2.6+/-1.4 mm Hg in the right and left eye, respectively). Correlation of mean diurnal IOP reduction between 2 one-eye trials was poor (r2=0.102), even after subtracting the nontreated eye IOP fluctuations from the treated eye IOPs (r2=0.097), but that between fellow eyes in bilateral treatment was excellent (r=0.849). Correlation of baseline IOP at each time point between fellow eyes in one-eye trials and bilateral treatment (r2=0.729 to 0.949) was better than that in the same eye between 2 one-eye trials (r2=0.319 to 0.631)., Conclusions: Fellow eyes in normal subjects showed a symmetrical IOP response to short-term bilateral treatment with latanoprost, although they did not respond symmetrically to one-eye trials performed separately for each eye. Poor correlation of IOP changes between 2 one-eye trials may be caused by different IOP responsiveness to latanoprost at each trial, rather than asymmetrical IOP fluctuations.

Purpose: To evaluate the relationship between polymorphisms of the prostaglandin F(2alpha) receptor (FP receptor) gene and the effectiveness of topical latanoprost treatment in normal volunteers., Design: Prospective nonrandomized trial., Participants: One hundred normal volunteers were recruited into the study., Methods: Baseline intraocular pressures (IOPs) of both eyes of 100 normal subjects were measured at 3 time points. Latanoprost (0.005%) was applied to one eye once daily for 7 days. Diurnal IOP was measured again on day 7. Response to latanoprost was evaluated by percent IOP reduction in the treated eye minus IOP fluctuations of the nontreated eye. We classified subjects by the mean diurnal percent IOP reduction (%DeltaIOP) into 3 groups: low responders (%DeltaIOP<10), medium responders (10< or =%DeltaIOP<25), and high responders (%DeltaIOP> or =25). Single-nucleotide polymorphisms (SNPs) in the FP receptor gene were searched, and the genotype was determined mainly by direct DNA sequencing. A promoter assay with a reporter luciferase gene was also performed., Main Outcome Measures: Mean diurnal percent IOP reduction and genotyping of SNPs in the FP receptor gene., Results: Ten SNPs were identified in this study. One, rs3753380, was located in the promoter region of the FP receptor gene and was significantly correlated with %DeltaIOP (CC, 20.3%+/-1.5% [mean +/- standard error]; CT + TT, 15.6%+/-1.2%; P = 0.0316). Mean diurnal percent IOP reduction was not associated with the other SNPs. When the category classified by %DeltaIOP was analyzed, not only rs3753380 but also rs3766355, an SNP in intron 1, were associated with the degree of response to latanoprost. The promoter assay revealed that the C allele of rs3766355 and T allele of rs3753380 were found in constructs with lower transcriptional activity of the FP receptor gene., Conclusions: rs3753380 and rs3766355, SNPs in the promoter and intron 1 regions of the FP receptor gene, correlate with a response to short-term latanoprost treatment in normal volunteers. The genotype of these SNPs may be an important determinant of variability in response to latanoprost.

Purpose: The present study in a mouse model was undertaken to reveal the role of the circadian clock genes Cry1 and Cry2 in generation of 24-hour intraocular pressure (IOP) rhythm., Methods: IOP was measured at eight time points daily (circadian time [CT] 0, 3, 6, 9, 12, 15, 18, and 21 hours), using a microneedle method in four groups of C57BL/6J mice (groups 1 and 3, wild-type; groups 2 and 4, Cry-deficient [Cry1-/-Cry2-/-]). During the IOP measurements, mice in groups 1 and 2 were maintained in a 12-hour light-dark cycle (LD), whereas mice in groups 3 and 4 were kept in a constant darkness (DD) that started 24 to 48 hours before the measurements. Circadian IOP variations in each group were evaluated by one-way analysis of variance (ANOVA) and Scheffé tests., Results: In wild-type mice living in LD conditions, pressures measured in the light phase were significantly lower than those in the dark phase. This daily rhythm was maintained under DD conditions with low pressure in the subjective day and high pressure in the subjective night. In contrast, Cry-deficient mice did not show significant circadian changes in IOP, regardless of environmental light conditions., Conclusions: These findings demonstrate that clock oscillatory mechanisms requiring the activity of core clock genes are essential for the generation of a circadian rhythm of intraocular pressure.

We retrospectively investigated the long-term effects of isopropyl unoprostone monotherapy on intraocular pressure and visual field for normal-tension glaucoma and primary open-angle glaucoma patients. Among 80 eyes of 49 subjects receiving isopropyl unoprostone monotherapy for 2 years or more, 32 eyes of 32 subjects were analyzed because of the good reliability of their visual acuity and visual field (age, 68.1 +/- 10.1 yrs, follow-up period 47.8 +/- 14.7 months). The mean values of intraocular pressure and visual field indices were compared with baseline data before medication. The visual field changes were also analyzed using the Kaplan-Meier life-table method. The mean intraocular pressure decreased for 4 years from 14.7 +/- 4.3 mmHg (mean +/- SD) at baseline, to 12.7 +/- 4.4mmHg at 4 years. The global index of visual field (mean defect, loss variance) did not change significantly during the 4 years. The accumulative probability of survival was 80.7 +/- 8.0% after 4 years when the endpoint was defined as 3dB progression in mean defect. Isopropyl unoprostone might have the possibility of stabilizing the visual field for a long period of time.

Purpose: To determine the reliability of noncontact tonometry (NCT) in measuring intraocular pressure (IOP) over a combination of amniotic membrane (AM) patch and therapeutic soft contact lens (TSCL) in normal human eyes., Design: Experimental study., Methods: Twenty-five healthy volunteers (twenty males, five females) participated in this study. After topical anesthesia, IOP was measured using noncontact tonometry before and after the application of a single layer of AM to the right eye and a double layer of AM to the left eye. To enable the IOP measurement by NCT, a TSCL was placed over the AM patch. The thickness of a single or a double layer of AM was measured by pachymetry and correlated with the IOP reading., Results: We found no statistical difference between IOPs measured with and without a combination of a single-layer AM/TSCL (P = .734). In contrast, the IOPs measured over a combination of a double-layer AM/TSCL decreased significantly when compared with the control (P < .0001). The average thicknesses of the single and the double layer of AM were 72.4 +/- 15.0 mum and 126.9 +/- 14.6 mum (mean +/- SD), respectively. There was a negative correlation between total AM thickness and IOP change (r = -.481, P = .0008)., Conclusions: We found that it is reliable to measure IOP by NCT through a combination of a single-layer AM/TSCL on normal human eyes. However, IOP measured by NCT over a combination of a double-layer AM/TSCL was inaccurate and tended to be an underestimation.

Purpose: To determine the reliability of Tono-Pen XL in measuring intraocular pressure (IOP) over the amniotic membrane patch in human eyes., Method: Ten healthy volunteers (nine males and one female) participated in this study. After topical anesthesia, IOP was measured using the Tono-Pen XL before and after the application of a single-layer amniotic membrane patch in the right eye and double-layer amniotic membrane patch in the left eye., Results: We found no statistical difference between the IOP measured with and without a single layer amniotic membrane (P = 0.808). Nor did we find any statistical difference between the IOP measured with and without double-layer amniotic membrane patch (P = 0.813). The average thickness of the single- and the double-layer amniotic membrane patch measured by pachymetry was 131.9 +/- 31.4 microm (mean +/- SD) and was 246.1 +/- 69.3 microm (mean +/- SD), respectively., Conclusions: This study showed that it is reliable to measure IOP by Tono-Pen XL over single or a double layer of amniotic membrane patch on healthy human eyes. Further studies are required to determine the accuracy of IOP measurement over amniotic membrane patch on diseased corneas.

We have tested the effect of topical administration of 0.5% para-amino-clonidine (PAC), an adrenergic alpha 2 agonist, on intraocular pressure (IOP), protein and prostaglandin E2 (PGE2) concentration in aqueous humor following the laser application to the iris of albino rabbits. The irides received Q-switched Nd: YAG laser irradiation with the energy level ranging from 2 to 80 mJ with and without topical administration of PAC one-hour prior to and immediately following laser irradiation. The IOP was measured with an Alcon pneumotonometer prior to and hourly for 6-hours following laser application. Aqueous humor was withdrawn prior to and at 0.5, 1, 2, 4 hours following laser irradiation for determining protein (Lowry method) and PGE2 (radioimmunoassay). Four to 6 rabbits were used for each experiment. The increase in IOP, protein and PGE2 concentration following laser irradiation was demonstrated to be dependent on the amount of laser energy. PAC significantly suppressed the IOP rise and the elevation of protein content, while it failed to affect the increase in PGE2.

Purpose: To examine the effects of nitric oxide synthase (NOS) inhibitors on intraocular pressure (IOP) and ocular inflammation following laser irradiation of the rabbit iris, and to investigate the involvement of nitric oxide (NO)., Methods: Thirty min after the intravenous administration of a nonselective inhibitor of NOS, N omega-nitro-L-arginine methyl ester (L-NAME, 1-100 mg/kg), or a selective inhibitor of iNOS, aminoguanidine (AG, 100 mg/kg), Q-switched Nd:YAG laser irradiation was applied to the iris of albino rabbits at an energy level of 48 mJ. IOP was measured prior to and for 24 h after irradiation. In separate groups of rabbits, aqueous humor was withdrawn 30 min after irradiation to determine protein and prostaglandin (PG) E2 concentrations., Results: Intravenously administered L-NAME dose-dependently inhibited the acute increase in IOP, the peak of which was observed at 30 min, following laser irradiation. The IOP increase was completely abolished by 100 mg/kg of L-NAME. This dose of L-NAME significantly reduced the elevation of protein concentration in aqueous humor following irradiation; however, this dose failed to affect the increase in PGE2 concentration On the other hand, the inhibitory effects of AG (100 mg/kg) on the increase in IOP and aqueous protein following laser irradiation were not significant., Conclusions: Intravenous administration of L-NAME significantly inhibits the IOP rise and the increase in protein concentration in aqueous humor following laser irradiation, but AG does not, suggest the involvement of cNOS in these ocular responses to laser irradiation.

This study was performed to clarify the ocular hypotensive mechanism of topical isopropyl unoprostone (unoprostone), a novel prostaglandin (PG) metabolite-related drug, in the rabbit eye. The intraperitoneal administration of indomethacin (50 mg/kg) 1 hour before administration of topical 0.12% unoprostone partially diminished the intraocular pressure (IOP) reduction, and completely blocked the increase in aqueous PGE2 concentration caused by unoprostone. Aqueous humor dynamics measurements in the unoprostone- and the vehicle-treated contralateral eyes with indomethacin pretreatment revealed that aqueous flow determined by fluorophotometry was not significantly different, 2.3 +/- 0.3 and 2.4 +/- 0.2 microliters/min, respectively; the total outflow facility measurements determined by the two-level constant pressure perfusion method were 0.20 +/- 0.01 and 0.14 +/- 0.01 microliters/min/mmHg, respectively (p < 0.05); the uveoscleral outflow measurements determined by the fluorescein isothiocyanate-dextran perfusion method were 0.49 +/- 0.02 and 0.46 +/- 0.02 microliters/min, respectively (p < 0.05). The magnitude of the IOP reduction induced by unoprostone was estimated to be 5.2 mmHg, which agrees well with the actual IOP reduction. In conclusion, unoprostone lowers the IOP by affecting aqueous outflow pathways, primarily the pressure-dependent conventional pathway and the secondary uveoscleral outflow pathway in rabbits. Endogenous PGs induced by topical unoprostone are also involved in lowering the IOP in rabbits.

This study attempted to clarify the role of endothelin A and B (ETA and ETB) receptors in modulating aqueous humor dynamics in the rabbit eye. Intraocular pressure (IOP), aqueous flow, total outflow facility, and uveoscleral outflow were measured before, and 24 hours after, intravitreal injection (20 microliters) of a selective ETB agonist, sarafotoxin S6c (SRTX S6c, 10(-5) M), into one eye and its vehicle into the contralateral eye. The measurements were also performed before and after injection of a selective ETA antagonist, 97-139 (10(-2) M) + ET-1 (10(-5) M) into one eye, and vehicle + ET-1 (10(-5) M) into the contralateral eye. In the SRTX S6c-treated eye, total outflow facility increased significantly by 106% compared with that in the vehicle-treated eye 24 hours after injection; aqueous flow and uveoscleral outflow failed to change significantly. The ETA antagonist 97-139 inhibited the decrease in aqueous flow partially, but significantly, but failed to inhibit the increase in total outflow facility caused by ET-1. Therefore, both ETA and ETB play a significant role in modulating aqueous humor dynamics in the rabbit eye. ETA can modulate aqueous humor production, at least in part. ETB can modulate total outflow facility, and the possibility for ETB in modulating aqueous humor formation cannot be ruled out.

Endothelin-1 (ET-1) is known to affect the intraocular pressure (IOP) in rabbits. We reported that intravitreally administered ET-1 induced biphasic IOP response, an early transient IOP rise followed by a subsequent prolonged decrease. In an attempt to clarify the role of ET receptor subtypes in the IOP responses following ET-1 injection, we studied the effects of ETA receptor-specific antagonist, BQ-123, in rabbits. We also evaluated the possible role of prostaglandins (PGs) and the disruption of the blood-aqueous barrier (BAB) following ET-1 injection in modulating the IOP change. BQ-123 (126.5 or 12.6 micrograms) was injected into the vitreous (20 microL/eye) of one eye in a group of 5 rabbits. Contralateral eyes received the same amount of vehicle in a masked randomized fashion. The same amount of ET-1 (0.5 or 0.05 micrograms) was injected intravitreally 30 minutes later into both eyes. IOP was measured prior to and periodically up to 120 hours after injection using a calibrated pneumatonometer. In another experiment BQ-123 (126.5 micrograms) was injected into one eye of 4 rabbits and the other eye served as a control to observe the effect of BQ-123 on the IOP. One hour and 24 hours following the injection of BQ-123 and ET-1, approximately 100 microL of aqueous humor was withdrawn by paracentesis. Protein concentration was measured by Lowry's method and PGE2 concentration, by radioimmunoassay. BQ-123 had no effect on the IOP when used alone. When used in combination with ET-1, BQ-123 (126.5 micrograms) significantly inhibited both the IOP rise (0.5-1 hour) and the reduction (24-72 hours) caused by ET-1 (0.5 microgram). BQ-123 (12.6 micrograms) also significantly inhibited the IOP reduction (6-8 hours and 72-96 hours) caused by ET-1 (0.05 micrograms). Pre-injection of BQ-123 (126.5 micrograms) significantly suppressed the increase in the aqueous protein and the PGE2 concentration both at 1 and 24 hours. The IOP response and the elevation of aqueous protein and PGE2 concentration following ET-1 injection are at least partly mediated by ETA receptors.

Endothelin-1 (ET-1) affects intraocular pressure (IOP) in rabbits. First, we studied IOP responses to the intravitreal injection of various doses of ET-1 ranging from 5 ng to 5 micrograms in unanesthetized rabbits, and observed a transient rise in IOP, from 0.5 to 2 h in duration, invariably followed by a prolonged IOP reduction, lasting for more than 72 h in rabbits treated with 0.5 microgram and 5 micrograms of ET-1. ET-1 (0.05 microgram and 0.15 microgram) resulted in a prolonged IOP reduction without an early IOP rise. Both IOP rise and reduction were significantly related to the dose of ET-1. A masked, randomized, study revealed that the intraperitoneal administration of indomethacin (50 mg/kg) prior to ET-1 injection significantly reduced the ocular hypertensive response, but not th ocular hypotensive response, to ET-1. The ETA receptor selective antagonist, 97-139 (155 micrograms) had no effect on IOP when used alone. However, when used in combination with 0.5 microgram of ET-1, 97-139 significantly inhibited both the IOP rise (0.5-2 h) and reduction (8-96 h) caused by ET-1. The ETB receptor selective agonist, sarafotoxin S6c (0.5 microgram), caused a sustained IOP reduction of 2 to 96 h in duration without the initial IOP rise. We also determined the concentration of prostaglandin (PG) E2 in the aqueous humor using radioimmunoassay techniques on samples obtained at 1 and 24 h after ET-1 injection, and examined the effects of pretreatment with indomethacin or 97-139 on PGE2 concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

We studied intraocular pressure (IOP) response to an intravitreal injection of 10(-5)M (20 microliters) endothelin-1 (ET-1) in unanesthetized rabbits, and found a transient IOP rise followed by a prolonged IOP reduction. ET-1 (10(-6)M) caused a sustained IOP reduction without an initial IOP rise. The ETA receptor selective antagonist, 97-139 (10(-2)M, 20 microliters), had no effect when used alone; however, when used in combination with ET-1 (10(-5)M), 97-139 (10(-2)M) significantly blocked the ocular hypotensive response to ET-1. 97-139 (10(-3)M), when used with 10(-6)M ET-1, also suppressed the IOP reduction induced by ET-1. Aqueous prostaglandin (PG) E2, determined by radioimmunoassay, was significantly elevated following intravitreal injection of ET-1 (10(-5)M). Prior injection of 97-139 (10(-2)M) significantly suppressed the elevation of aqueous PGE2 concentration caused by ET-1 (10(-5)M). These results suggest that both the IOP response and the elevation of aqueous PGE2 following ET-1 injection are at least partially mediated by ETA receptor.

The authors have reported that ET-1 and ETB receptor agonist, sarafotoxin S6c (STX-S6c), caused prolonged intraocular pressure (IOP) reduction in rabbit eyes in a dose-dependent fashion when injected intravitreally. The purpose of this study was to determine the effects of STX-S6c on the blood-aqueous barrier and also the possible role of cyclooxygenase products in modulating IOP. Indomethacin, a cyclooxygenase inhibitor (50 mg/kg), or its placebo was administered intraperitoneally 1 hour before or 1 hour before and 4 hours after the intravitreal injection of 0.5 micrograms of STX-S6c into one eye in a group of albino rabbits. The fellow eye received the vehicle only. IOP was measured prior to and periodically up to 120 hours after the injection using a calibrated pneumatonometer. One hour and 24 hours following the injection of STX-S6c (0.5 micrograms) with or without indomethacin, approximately 100 microL of aqueous humor was withdrawn by paracentesis. Protein concentration was measured by Lowry's method and PGE2 concentration was determined by radioimmunoassay. Both single and double dosings of indomethacin failed to prevent the IOP reduction caused by STX-S6c. The eyes injected with STX-S6c exhibited a significant elevation of both PGE2 and protein concentration at both 1 and 24 hours after injection. Pretreatment with indomethacin could significantly suppress the PGE2 and protein content of aqueous humor at both 1 and 24 hours after injection. ETB receptor agonist, STX-S6c, appears to induce the IOP reduction without affecting the cyclooxygenase pathway or disrupting the blood-aqueous barrier.

Endothelin-1 (ET-1) reduced intraocular pressure (IOP) in animals when administered topically. The time-course of IOP changes induced by ET-1, however, has not been fully documented. We studied the IOP response to different doses of intravitreally injected ET-1 ranging from 10(-7) to 10(-4) M in rabbits. In each animal one eye received 20 muL of ET-1 solution and the contralateral eye received the same amount of vehicle in a randomized, masked fashion. IOP was measured by a pneumatonometer prior to and periodically for at least 72 hours after the intravitreal injection. ET-1 in 10(-4) and 10(-5) M concentration elicited an IOP response consisting of an initial rise of 1- to 2-hour duration, and a subsequent prolonged reduction lasting for more than 72 hours. The use of 3 x 10(-6) and 10(-6) M solutions resulted in a prolonged IOP reduction without an early IOP rise. No significant IOP change was induced by 10(-7) M solution or the vehicle. No change was observed in pupillary diameters after injection of ET-1 in any dose. The aqueous prostaglandin E2 concentration was significantly increased at both 1 and 24 hours after 10(-5) M ET-1 injection.

Endothelin-1 (ET-1) reduces intraocular pressure (IOP) in animals when administered topically. The time course of IOP induced by ET-1, however, has not been fully elucidated. We studied the IOP response to different doses of ET-1 ranging from 10(-7) to 10(-4)M (5 micrograms to 5 ng) intravitreally injected in rabbits. In each animal one eyes received 20 microliters of ET-1 solution and the contralateral eye received same amount of vehicle in a randomized, masked fashion. IOP was measured by a pneumotonometer prior to and periodically for at least 72 hours after the intravitreal injection. ET-1 in 10(-4) and 10(-5) molar concentration elicited a biphasic IOP response consisting of an initial rise of 1 to 2 hours duration, and a subsequent prolonged reduction lasting for more than 72 hours. 3 x 10(-6) and 10(-6) M solution resulted in a prolonged IOP reduction without an early IOP rise. No significant IOP change was induced by 10(-7) M solution or vehicle. Both IOP rise and reduction were significantly related to the dose of ET-1.

The effects of endothelin-1 (ET-1) on intraocular pressure (IOP) and aqueous humor dynamics were studied in the rabbit eye. The intravitreal injection of 10(-5) M ET-1 (20 microliters) produced a biphasic IOP response consisting of an initial rise of 1 to 2 hours in duration, and a subsequent prolonged reduction lasting for more than 96 hours. Aqueous humor dynamics were determined 24 hours after the 10(-5) M ET-1 injection. Aqueous humor formation, measured fluorophotometrically, was decreased by 58%. Total outflow facility increased by 94%, according to measurement by two-level constant pressure perfusion. The change of uveoscleral outflow determined by fluorescein-dextran perfusion was not significant. The decrease in aqueous flow and the increase in total facility accounted for most of the IOP reduction after the ET-1 injection. Endothelin, which is endogenously present in the eye, may play a role in the regulation of intraocular pressure.

In rabbits, laser irradiation of the iris causes an immediate rise in intraocular pressure (IOP), with a concomitant increase of prostaglandins (PGs) in the aqueous humor. We studied IOP responses to Q-switched Nd:YAG laser application to the iris in unanesthetized rabbits, and found that a prolonged IOP reduction lasting for 6-24 hr invariably followed the transient IOP rise of 0.5-2 hr duration. The magnitude of both the IOP rise and reduction was dependent on the level of laser energy. A masked, randomized study revealed that the intraperitoneal administration of indomethacin (50 mg kg-1) prior to laser application significantly reduced the ocular hypertensive and hypotensive responses to laser irradiation (energy: 24 mJ). The maximum IOP rise from baseline was 5.4 +/- 3.0 mmHg (n = 10) with the intraperitoneal vehicle and 1.5 +/- 4.2 mmHg (n = 10) with intraperitoneal indomethacin administration. Thus, the difference was statistically significant (P less than 0.025, Student's t-test). The maximum IOP reduction from baseline was -8.5 +/- 2.6 mmHg (n = 10) with the intraperitoneal vehicle and -4.0 +/- 2.4 mmHg (n = 10) with intraperitoneal indomethacin (P less than 0.001, Student's t-test). The concentration of PGE2 in the aqueous humor, as determined by radioimmunoassay on samples obtained at 2 and 4 hr after laser application, was found to be significantly increased in rabbits that received the vehicle solution but not in animals that were pretreated with intraperitoneal injection of indomethacin. This suggests that this PG or other cyclooxygenase products are involved with mediation of the initial IOP increase and the prolonged decrease in IOP that follows laser irradiation of the iris.

8-hydroxycarteolol hydrochloride (8-OH carteolol) is a main metabolite of carteolol hydrochloride (carteolol). We conducted a randomized double-masked single-drop study in an attempt to compare the effects of the ophthalmic solution of 8-OH carteolol and carteolol on intraocular pressure (IOP) in rabbits with water-load and monkeys. Both 8-OH carteolol (0.01 and 0.1%) and carteolol (1 and 2%) suppressed the water-load induced IOP rise in rabbits. 8-OH carteolol was more effective in suppressing the water-load induced IOP rise in rabbits compared with carteolol on equimolar basis. Both 8-OH carteolol (0.1%) and carteolol (2%) caused a statistically significant decrease in IOP in monkeys. 8-OH carteolol was estimated to be more potent than carteolol in lowering IOP on equimolar basis in monkeys.

We evaluated the ability of topical clonidine to suppress an acute rise in postoperative intraocular pressure (IOP) following Nd:YAG laser iridotomy. A total of 36 eyes (29 patients) with chronic primary angle-closure glaucoma underwent Q-switched Nd:YAG laser iridotomy: 18 eyes were treated topically with 0.5% clonidine ophthalmic solution prior to and immediately following the procedure, and a control group of 18 eyes underwent Nd:YAG laser iridotomy without topical clonidine. The control group was selected to match the clonidine-treated group in terms of preoperative IOP, the extent of peripheral anterior synechia, and the total amount of laser energy delivered. None of the clonidine-treated eyes experienced an IOP rise greater than 4 mm Hg over baseline, whereas 4 of the nontreated eyes (22.2%) developed an IOP rise greater than 10 mm Hg. The mean IOPs were significantly lower during the first 4 h postsurgery in the clonidine-treated eyes.

Daisuke Takemoto, Tomomi Higashide, Yoshiaki Saito, Shinji Ohkubo, Sachiko Udagawa, Hisashi Takeda, Kazuhisa Sugiyama Department of Ophthalmology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan Purpose: We conducted a prospective study in patients with normal-tension glaucoma (NTG) who received either isopropyl unoprostone or latanoprost. We compared the drugs in terms of their effects on intraocular pressure (IOP) and visual field loss progression over a 3-year period. Study design: Prospective, randomized controlled study. Methods: We enrolled 48 patients with newly diagnosed NTG at Kanazawa University Hospital. Eligible patients were randomly allocated (1:1) to receive either unoprostone or latanoprost ophthalmic solutions. The primary outcomes were IOP changes and visual field deterioration within 36 months. Visual field changes were analyzed: the cumulative survival rates were calculated in terms of mean deviation, pattern standard deviation, and total deviation of the upper or lower hemi-visual field, each visual field sector, and guided progression analysis. In addition, we evaluated the progression of glaucomatous optic disc changes using fundus photography and confocal scanning laser ophthalmoscopy. Results: The mean pretreatment IOP was 15.0±2.4 mmHg in the Unoprostone group and 15.2±1.9 mmHg in the Latanoprost group. The mean IOP during the treatment period was 13.7±2.3 mmHg in the Unoprostone group and 13.0±1.8 mmHg in the Latanoprost group. In both groups, the IOP decreased significantly (p