Effects of prostaglandin F(2α) analogues on endothelin-1-induced impairment of rabbit ocular blood flow: comparison among tafluprost, travoprost, and latanoprost.

We investigated the effects of prostaglandin F(2α) (PGF(2α)) analogues on the endothelin-1 (ET-1)-induced impairment of optic nerve head (ONH) blood flow and on ET-1-induced contraction in isolated ciliary artery segments. In male rabbits, one of four PGF(2α) analogues [0.0015% tafluprost, 0.0015% 15-hydroxyl tafluprost (15-OH tafluprost), 0.005% latanoprost, or 0.004% travoprost] was topically administered at various pretreatment times before intravitreal ET-1 injection. ONH blood flow was estimated by the laser speckle method, which expresses blood velocity as a quantitative index, the squared blur rate (SBR). SBR was measured just before (baseline value) and at 30, 60, and 120 min after ET-1 injection. SBR was significantly decreased from 4.47 ± 0.20 to 3.50 ± 0.10 (78.6 ± 2.4% of baseline) at 120 min after intravitreal ET-1 injection (5 pmol/eye). The ET-1-induced decrease was almost completely prevented by tafluprost and significantly inhibited by the other three analogues. The inhibitory effect lasted longest with tafluprost, as indicated by the effective pretreatment times (tafluprost: 90, 120, or 240 min; 15-OH tafluprost: 90, but not 120 or 240 min; latanoprost and travoprost: 120, but not 240 min). In vitro, the effects of PGF(2α) analogues on ET-1-induced contractions in male rabbit ciliary arteries were evaluated using an isometric tension recording system. Tafluprost, latanoprost, travoprost, and 15-OH tafluprost concentration-dependently relaxed the 10 nM ET-1-induced ciliary artery contraction. Improvement of the ocular circulation may be superior with tafluprost than with the other PGF(2α) analogues. The underlying mechanism may involve relaxation of ocular resistance vessels.

Predicting Lifetime Transition Risk of Severe Visual Field Defects Using Monte Carlo Simulation in Japanese Patients with Primary Open-Angle Glaucoma.

PURPOSE: To maintain visual fields and quality of life over a lifetime, medical practice must be conducted taking into consideration not only visual field progression but also future visual field changes that occur over the patients' expected lifespan. The purpose of this study is to investigate the feasibility of establishing a model that predicts prognosis, estimating the proportion of glaucoma patients with severe visual field defects. PATIENTS AND METHODS: The data of 191 patients with primary open-angle glaucoma, with a predominance of normal-tension glaucoma, were used for this study. The model was developed based on patients' backgrounds and risk factors, using Monte Carlo simulation. A "severe visual field defect" was defined as ≤-20 dB. The mean deviation (MD) value for 10,000 virtual patients in each simulation pattern (144 patterns) was calculated using a predictive formula to estimate the MD slope, and the effects of risk factors and intraocular pressure (IOP) reduction on the proportion of patients with severe visual field defects were evaluated. RESULTS: Younger age, later-stage disease, more severe glaucomatous structural abnormalities and the presence of disc hemorrhage were associated with an increase in the progression rate of patients with severe visual field defects. Conversely, lower IOP was associated with a decrease in this rate. CONCLUSION: Combining regression analysis with Monte Carlo simulation could be a useful method for developing predictive models of prognosis in glaucoma patients.

Preperimetric Glaucoma Prospective Study (PPGPS): Predicting Visual Field Progression With Basal Optic Nerve Head Blood Flow in Normotensive PPG Eyes.

PURPOSE: To investigate the site specificity of visual field changes in eyes with normotensive preperimetric glaucoma (PPG), and to determine factors influencing visual field progression. METHODS: This prospective study comprised 84 eyes of 84 normotensive PPG patients followed for at least 16 months. Optic nerve head (ONH) blood flow was assessed with tissue-area mean blur rate (MBRT), derived from laser speckle flowgraphy. Total deviation (TD) was measured in each sector of the Garway-Heath map to evaluate the site specificity of visual field loss. Subjects with a TD slope in the first quartile were classified as progressive, and other subjects as nonprogressive. Linear and multiple regression analyses were performed to determine factors affecting visual field progression. RESULTS: TD in the superior sector significantly decreased in the subjects overall during the follow-up periods (-0.48 ± 1.92 dB/y, P = 0.025). Linear regression analysis showed that basal MBRT-inferior was correlated significantly with TD-superior slope (r = 0.332, P = 0.002). Furthermore, basal MBRT was significantly lower in this sector in the progressive than the nonprogressive group (P = 0.010). Multiple linear regression analysis revealed that basal MBRT-inferior was the only predictive factor for TD-superior slope (ß = 0.329, P = 0.005). CONCLUSIONS: These findings suggest that superior-sector visual field progression is most common in normotensive PPG eyes, and that reduced basal ONH blood flow is associated with visual field progression. TRANSLATIONAL RELEVANCE: These findings provide new insight into the involvement of ONH blood flow impairment in glaucoma pathogenesis, and demonstrate the importance of assessing ONH blood flow to determine visual field progression in normotensive PPG.

Prediction of Visual Field Progression in Patients with Primary Open-Angle Glaucoma, Mainly Including Normal Tension Glaucoma.

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.

Preperimetric Glaucoma Prospective Observational Study (PPGPS): Design, baseline characteristics, and therapeutic effect of tafluprost in preperimetric glaucoma eye.

PURPOSE: There is no consensus on the diagnosis or treatment policy for Preperimetric Glaucoma (PPG) because the pathogenesis of PPG is not clear at this time. Preperimetric Glaucoma Prospective Observational Study (PPGPS) is a first multicenter, prospective, observational study to clarify the pathogenesis of PPG. This article indicates study design, patient baseline characteristics, and analysis focused on optic nerve head (ONH) blood flow in PPG, as well as the intraocular pressure (IOP) -lowering effect and ONH blood flow-improving effects of Tafluprost. METHOD: In this study, 122 eyes from 122 subjects (mean age: 53.1 ± 14.3) newly diagnosed as PPG were enrolled. The circumpapillary retinal nerve fiber layer thickness (cpRNFLT) was evaluated with optical coherence tomography (OCT). The ONH blood flow was measured with laser speckle flowgraphy. The therapeutic effect of Tafluprost was evaluated at Month 0 (ONH blood flow-improving effect) and Month 4 (IOP-lowering effect). RESULTS: The untreated IOP, cpRNFLT, and baseline Mean deviation (MD) value was 16.4 ± 2.5 mmHg, 80.4 ± 8.2 µm, and -0.48 ± 1.29 dB, respectively. In the site-specific visual field evaluation using the sector map, there was no appreciable site-specific visual field defect in the eye with PPG. The inferior region of cpRNFLT in 4-quadrant OCT sector analysis and 6 o'clock region in 12-o'clock OCT sector analysis was the highest rate of abnormality in PPG eyes. Topical administration of Tafluprost significantly reduced IOP from 16.4 ± 2.5 mmHg at baseline to 14.5 ± 2.3 mmHg at Month 4 (P < 0.001, paired t-test). In the linear regression analysis, there was a significant relationship between the increase of ONH blood flow and baseline value. CONCLUSION: PPGPS is a first prospective study focusing on the pathology of PPG. This study is expected to elucidate the pathology of PPG, with evidence useful for determining a treatment strategy for PPG.

2-Phenyl-APB-144-Induced Retinal Pigment Epithelium Degeneration and Its Underlying Mechanisms.

PURPOSE: To investigate the efficacy of 2-phenyl-APB-144 (APB)-induced retinopathy in a rat model and its underlying mechanisms, with a particular focus on retinal pigment epithelium (RPE) degeneration. METHODS: Electroretinograms (ERGs) were evaluated in APB-administered rats. In ARPE-19 cells, cathepsin, and autophagy marker LC3 were analyzed by western blotting or immunohistochemistry. Organelle pH alterations were detected by Acridine Orange Staining. Endoplasmic reticulum stress-dependent or -independent cell death signaling was analyzed by reporter gene assays of activating transcription factor 4 (ATF4), immunoglobulin heavy-chain binding protein (BiP), inositol-requiring enzyme 1α (IRE1α), quantitative reverse transcription-polymerase chain reaction of CHOP mRNA, and the effects of pharmacological eukaryotic initiation factor 2α (eIF2α) dephosphorylation inhibitor, Salubrinal. The pharmacological effects of Salubrinal were examined by fluorophotometry, electrophysiology, and histopathology. RESULTS: APB-induced ERG amplitude reduction and fluorescein permeability enhancement into the vitreous body of rats were determined. In ARPE-19 cells, APB-induced organelle pH alterations, imbalances of procathepsin and cathepsin expression, the time-dependent accumulation of LC3-II, and the translational activation of ATF4 were determined. Salubrinal protected against APB-induced cell death and inhibited ATF4 downstream factor CHOP mRNA induction. In APB-induced rat retinopathy, systemic Salubrinal alleviated the enhanced fluorescein permeability into the vitreous body from the RPE, the reductions in ERG amplitudes, and RPE degeneration. CONCLUSIONS: Organelle pH alterations and autophagy impairments are involved in APB-induced RPE cell death. Inhibition of eIF2α dephosphorylation protected the RPE in vivo and in vitro. These findings suggested that APB-induced retinopathy is a valuable animal model for exploring the mechanism of RPE-driven retinopathy.

Ocular hypotensive effect of tafluprost in latanoprost low-responder cynomolgus monkeys.

PURPOSE: To determine the proportion of latanoprost low-responders among cynomolgus monkeys, and to evaluate the switching efficacy from latanoprost to tafluprost in latanoprost low-responder monkeys. METHODS: Thirty-nine ocular normotensive monkeys were used in this study. Latanoprost low-responders were detected using a 2-step evaluation procedure. In the first step, the response to single administration of latanoprost was investigated in all monkeys. In the second step, the response to 7-day administration of latanoprost was evaluated in screened monkeys. We defined latanoprost low-responders as any monkey that showed intraocular pressure (IOP) reduction of 1 mm Hg or less during the 7-day treatment. Switching efficacy from latanoprost to tafluprost was then evaluated in a 3-phase switching study. Latanoprost was topically administered for about 1 week in phases 1 and 3, with tafluprost being topically administered for about 1 week in phase 2. RESULTS: Eleven monkeys were "latanoprost low-responders." The maximal IOP reduction exhibited by these low-responders in the second step of the evaluation was 0.5±0.2 mm Hg (mean±SEM) during saline treatment and 0.8±0.2 mm Hg during latanoprost treatment. In the 3-phase switching study, the maximal IOP reductions were: 0.4±0.2 mm Hg in phase 1 (latanoprost), 2.4±0.3 mm Hg in phase 2 (tafluprost), and 0.5±0.2 mm Hg in phase 3 (latanoprost). CONCLUSIONS: Latanoprost low-responders exist among cynomolgus monkeys. Switching from latanoprost to tafluprost reduced IOP, and tafluprost's IOP-lowering effect disappeared after switching back to latanoprost in the latanoprost low-responder monkeys. These results suggested that tafluprost might be effective for latanoprost nonresponder patients.

Effects of repeated administrations of tafluprost, latanoprost, and travoprost on optic nerve head blood flow in conscious normal rabbits.

PURPOSE: The aim of this study was to evaluate and compare the effects of repeated administrations of three prostaglandin F(2alpha) analogs (tafluprost, latanoprost, and travoprost) on optic nerve head (ONH) blood flow in normal rabbits. METHODS: Male Dutch rabbits were housed under a 12-h light-dark cycle for use in this study. A quantitative index of blood flow, the squared blur rate (SBR), was determined using laser speckle flowgraphy. Saline, 0.0015% tafluprost, 0.005% latanoprost, or 0.004% travoprost (each 50 microL) was topically administered into the left eye once daily for 28 days. ONH blood flow was measured before the start at the course of treatment (baseline), and on day 14 and/or day 28 [measurements being made at 0, 30, and/or 60 min after drugs application on day 14 and/or day 28]. Heart rate was also measured at these time points. RESULTS: Tafluprost, latanoprost, and travoprost each increased the ONH blood flow at all measurement points on day 14 and/or day 28. The 0 min SBR value on day 14 was greater than the baseline SBR value by 8.7% + or - 4.4% for tafluprost and by 5.8% + or - 1.7% for latanoprost. The 0 min SBR value on day 28 was greater than the baseline SBR value by 11.9% + or - 3.9% for tafluprost, by 7.2% + or - 4.3% for latanoprost, and by 6.7% + or - 3.5% for travoprost. The increasing state of the ONH blood flow continued within 60 min after a topical administration of tafluprost, latanoprost, or travoprost. Tafluprost, latanoprost, and travoprost did not change heart rate (vs. the baseline value) at any measurement points. CONCLUSIONS: Repeated topical administration of any of the three prostaglandin F(2alpha) analogs increased ONH blood flow in rabbits, without changing heart rate. The increase in ONH blood flow induced by tafluprost was greater than that induced by latanoprost (P = 0.086) or travoprost (P = 0.037) at 60 min on day 28.

The Response of Pseudomonas aeruginosa PAO1 Efflux Pump-Defective Mutants to N-Octanoyl-L-Homoserine Lactone.

N-Octanoyl-L-homoserine lactone (C8-HSL) is an acyl-homoserine-lactone signal utilized in the quorum-sensing (QS) systems of Burkholderia cenocepacia and other bacterial species. Although also produced by Pseudomonas aeruginosa, its role in this species has not been elucidated. Here, we report that C8-HSL modulated antibiotic resistance and pyocyanin production in a P. aeruginosa efflux pump-deficient mutant. The rhl/las quorum-sensing system and qscR gene were both shown to be nonessential in the C8-HSL-induced changes in ofloxacin resistance, suggesting that P. aeruginosa possesses a distinct pathway to respond to C8-HSL.