Pre-synchronization of ovulation timing and delayed fixed-time artificial insemination increases pregnancy rates when sex-sorted semen is used for insemination of heifers.

This study was conducted to determine effects of pre-synchronization of ovulation timing among heifers and delayed fixed-time artificial insemination (TAI) with sex-sorted semen on proportion of heifers pregnant after TAI (PR/AI). Heifers were assigned to one of eight treatments: 1 and 2), 7-d CO-Synch + CIDR treatment regimen with administration of gonadotropin-releasing hormone and a CIDR insert on Day 0, prostaglandin F2α (PGF) at CIDR removal on Day 7, and TAI occurring 54 h later with conventionally processed (CTRL54-CNV) or sex-sorted semen (CTRL54-SEX); 3 and 4), same as CTRL54 but TAI delayed to 72 h with conventionally processed (CTRL72-CNV) or sex-sorted semen (CTRL72-SEX); 5 and 6), same as CTRL54 but additional administration of PGF on Day -7 and TAI with conventionally processed (PRE54-CNV) or sex-sorted semen (PRE54-SEX); 7 and 8), same as PRE54 treatments but TAI delayed to 72 h with conventionally processed (PRE72-CNV) or sex-sorted semen (PRE72-SEX). Proportion of heifers pregnant after TAI was greater (P ≤  0.02) with conventionally processed semen compared with sex-sorted semen, yet PR/AI did not differ (P =  0.14) between heifers in PRE72-CNV and PRE72-SEX groups. There were greater PR/AI in the PRE72-SEX (P =  0.03) than CTRL54-SEX group (46.1 % and 36.9 %) and there was no difference (P =  0.31) in PR/AI between CTRL54-CNV and PRE72-SEX groups (50.4 % and 46.1 %). In conclusion, pre-synchronization of ovulation timing among heifers combined with delayed TAI resulted in increased PR/AI with sex-sorted semen compared with the 7-d CO-Synch+CIDR treatment regimen.

Effects of pupil size on canine visual evoked potential with pattern stimulation.

The purpose of this study was to investigate the effects of pupil diameter on canine visual evoked potentials with pattern stimulation (P-VEP). Atropine eye drop (1.0%) was applied to both eyes as a cycloplegic drug, and tafluprost eye drop (0.015%) was applied to one eye that was selected randomly for miosis (miosis group). The other eye did not receive tafluprost (mydriasis group). P-VEP was recorded at three pattern sizes. The P100 implicit time at a small pattern size in the mydriasis group was significantly prolonged compared to the miosis group. We hypothesized that the prolonged P100 implicit time under mydriatic conditions was due to increased spherical aberrations and concluded that mydriatic conditions affected P100 implicit time in canine P-VEP recordings.

Treatment of Open-Angle Glaucoma and Ocular Hypertension with Preservative-Free Tafluprost/Timolol Fixed-Dose Combination Therapy: The VISIONARY Study.

INTRODUCTION: A non-interventional, multicenter, European, prospective evaluation of the effectiveness, tolerability, and safety of a topical preservative-free tafluprost (0.0015%) and timolol (0.5%) fixed-dose combination (PF tafluprost/timolol FC) in adults with open-angle glaucoma (OAG) and ocular hypertension (OHT) demonstrating insufficient response to topical beta-receptor blockers or prostaglandin analogue (PGA) monotherapy. METHODS: Mean intraocular pressure (IOP) change from baseline was measured at study visits following a switch to PF tafluprost/timolol FC. Primary endpoint was absolute mean IOP change at month 6. Change from baseline concerning ocular signs and symptoms was also explored. RESULTS: Analyses included 577 patients (59.6% female). Mean age (SD) was 67.8 (11.67) years. Mean (SD) IOP reduction from baseline was significant at all study visits; 5.4 (3.76) mmHg (23.7%) at week 4, 5.9 (3.90) mmHg (25.6%) at week 12, and 5.7 (4.11) mmHg (24.9%) at month 6 (p < 0.0001 for all visits). At month 6, 69.2%, 53.6%, 40.0%, and 25.8% were responders based on ≥ 20%, ≥ 25%, ≥ 30%, and ≥ 35% cutoff values for mean IOP, respectively. Significant reductions were observed concerning corneal fluorescein staining (p < 0.0001), dry eye symptoms, irritation, itching, and foreign body sensation (p < 0.001 for each parameter). Conjunctival hyperemia was significantly reduced at all study visits (p < 0.0001 at each visit). Overall, 69 treatment-related adverse events (AEs) were reported, one of which was serious (status asthmaticus). Most AEs were mild to moderate in severity, and the majority had resolved or were resolving at the end of the study period. CONCLUSION: In clinical practice, PF tafluprost/timolol FC provided statistically and clinically significant IOP reductions in patients with OAG and OHT insufficiently controlled on or intolerant to PGA or beta-receptor blocker monotherapy. The full IOP reduction appeared at week 4 and was maintained over the 6-month study period. Key symptoms of ocular surface health improved. TRIAL REGISTRATION: European Union electronic Register of Post-Authorisation Studies (EU PAS) register number, EUPAS22204.

The Sustained Release of Tafluprost with a Drug Delivery System Prevents the Axonal Injury-induced Loss of Retinal Ganglion Cells in Rats.

PURPOSE: To investigated whether a new drug delivery system (DDS) could enable the controlled release of tafluprost and suppress retinal ganglion cell (RGC) death in rats after optic nerve transection (ONT). METHODS: A DDS containing 0.04%, 0.20% or 1.00% tafluprost, or vehicle, was injected intravitreally in 8-12-week-old male Sprague-Dawley rats 7 days before ONT, and the retinas were extracted 7 days after ONT. For comparison, eye drops containing 0.0015% tafluprost or vehicle were used once a day. The extracted retinas were analyzed with liquid chromatography-tandem mass spectrometry, immunohistochemistry and western blotting. RESULTS: The level of tafluprost acid in the groups that received the 0.20% and 1.00% tafluprost DDSs was stable, and higher than the maximum concentration in the eye drop group, even after 14 days. In the retinas treated with the 1.00% tafluprost DDS, the active form of the drug had a high concentration (~50 times higher than eye drops), but no significant IOP difference compared with its vehicle in this study. The 1.00% tafluprost DDS group also had less cleaved α-fodrin and fewer c-Jun-positive cells than the vehicle DDS group. CONCLUSIONS: This study found that a newly developed DDS allowed the controlled release of tafluprost and prevented the loss of RGCs after ONT IOP independently. The duration of drug action on the target site was longer with a tafluprost DDS than with topical instillation and should therefore reduce problems related to lack of patient compliance. This system may also enable new treatments to prevent RGC degeneration in diseases such as glaucoma.

Embryo collection from pigs post-pseudopregnancy induced by estradiol dipropionate.

We aimed to define whether embryo collection carried out after pseudopregnancy was of similar outcome and quality as after artificial abortion. To induce pseudopregnancy, 30 gilts or sows were given 20 mg intramuscular estradiol dipropionate (EDP) 10-11 days after the onset of estrus. Ten additional pigs were inseminated artificially at natural estrus as a control group. Prostaglandin F2α (PGF2α ) was administered twice with a 24 hr interval beginning 15, 20, or 25 days after EDP-treatment (n = 10 per group) or between 23 and 39 days after artificial insemination in control pigs. Following this, all pigs were given 1,000 IU equine chorionic gonadotropin and 500 IU human chorionic gonadotropin (hCG) and then inseminated. Embryos were recovered 6 or 7 days after hCG treatment and outcome was recorded. There was no significant difference in the number of normal embryos collected from the pigs with PGF2α initiated at different time points or from the control group. Embryonic developmental stages 7 days after hCG treatment also did not differ among groups. These results indicate that the use of EDP to induce pseudopregnancy, followed by PGF2α administration to synchronize estrus for subsequent embryo harvest, is a suitable alternative to the artificial abortion method.

Efficacy and safety of the fixed combinations of tafluprost/timolol and latanoprost/carteolol.

In this study, we made a comparative efficacy and safety assessment of two different fixed combinations of drugs, viz., tafluprost/timolol (TAF/TIM) and latanoprost/carteolol (LAT/CAR), by determining their effects on intraocular pressure (IOP) in ocular normotensive monkeys and examining their toxic effects on ocular surface using human corneal epithelial cells. TAF/TIM was found to be more effective in lowering IOP for a longer duration compared to LAT/CAR. We found that the difference in the intensity of IOP-lowering effect was because of the differences in the strength of timolol compared with that of carteolol as a beta-adrenergic antagonist and strength of tafluprost compared with that of latanoprost as a prostaglandin analogue. In addition, TAF/TIM showed much less cytotoxic effects compared to LAT/CAR on the human corneal epithelial cells. Our findings showed that TAF/TIM is better than LAT/CAR with regard to the IOP-lowering effect in monkeys and toxicity on ocular surface.

Comparison of different combinations of maximum medical therapy for lowering intraocular pressure in primary open angle glaucoma: 12-month retrospective consecutive case series.

PURPOSE: To compare the efficacy and safety of two combinations of maximum medical therapy for lowering intraocular pressure (IOP) in primary open angle glaucoma (POAG). STUDY DESIGN: A retrospective consecutive case series. METHODS: A retrospective consecutive case series study including 82 eyes of 82 subjects with POAG treated with maximum medical therapy to lower IOP. Enrolled patients were divided into 2 groups: the triple maximum medical therapy (TMT) group, comprising POAG patients who were treated with tafluprost, brimonidine and the fixed drug combination (FDC) brinzolamide/timolol; and the double maximum medical therapy (DMT) group, comprising POAG patients who were treated with the FDCs tafluprost/timolol and brinzolamide/brimonidine. We compared the demographics, baseline IOP, IOP reduction rate, and adverse drug reactions (ADRs) between the 2 groups. RESULTS: While the mean IOP reduction rate after 12 months was higher in the TMT group (52.7%) than in the DMT group (50.4%), the difference was not significant (p-value = 0.615). In the TMT group, the rate of proceeding to laser or surgical therapy was 22.2% (DMT group = 37.8%). In the TMT group, the time duration between beginning maximum medical therapy and proceeding to laser or surgical therapy was 10.7 ± 1.3 months (DMT group = 10.3 ± 1.5 months). No serious ADRs were reported in either group. However, the incidence rate of conjunctival hyperemia and dry eye was significantly lower in the DMT group than in the TMT group. CONCLUSION: DMT is safe and effective for lowering IOP in POAG patients. DMT is not inferior to TMT in POAG patients.

Changes in ocular signs and symptoms in patients switching from bimatoprost-timolol to tafluprost-timolol eye drops: an open-label phase IV study.

OBJECTIVES: Bimatoprost-timolol (bimatoprost 0.03%-timolol 0.5% fixed-dose combination [FDC]) and tafluprost-timolol (tafluprost 0.0015%-timolol 0.5% FDC) eye drops are currently the only topical intraocular pressure (IOP)-reducing therapies available as preservative-free (PF) prostaglandin and timolol FDC. The aim of this study was to investigate changes to ocular signs and symptoms when patients with ocular hypertension (OH) or open-angle glaucoma (OAG) switched from PF or benzalkonium chloride (BAK)-preserved bimatoprost-timolol to PF tafluprost-timolol eye drops. DESIGN: This was a 12-week, open-label, phase IV study. SETTING: Sixteen centres in Finland, Germany, Italy and the UK. PARTICIPANTS: Patients with OH or OAG (IOP on medication ≤21 mm Hg), treated with PF or BAK-preserved bimatoprost-timolol for ≥4 weeks before screening, and presenting with conjunctival hyperaemia and ≥1 ocular symptom. INTERVENTIONS: Patients were switched to PF tafluprost-timolol once daily in the treated eye(s). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary endpoints were change from screening to week 12 in conjunctival hyperaemia and worst ocular symptom. The secondary outcome measures were changes from screening in ocular signs (other than conjunctival hyperaemia) and symptoms at week 12. RESULTS: Of 123 enrolled patients, 121 were included in the intention-to-treat dataset, of which all were Caucasian and 54.5% were female; 76 patients used BAK-preserved bimatoprost-timolol and 45 used PF drops. Conjunctival hyperaemia and severity of worst ocular symptom following switch to PF tafluprost-timolol significantly reduced from screening to week 12 in all patients (p<0.001). The percentage of patients with ocular signs and symptoms was significantly reduced at week 12 compared with screening (p<0.001). IOP was not affected by the change of treatment. CONCLUSIONS: Switching from BAK-preserved or PF bimatoprost-timolol to tafluprost-timolol reduced both signs and symptoms of ocular surface disease with no clinically relevant effect on IOP. TRIAL REGISTRATION NUMBER: EudraCT2014-005273-37; Results.

Preservative-free tafluprost/timolol fixed combination: comparative 24-h efficacy administered morning or evening in open-angle glaucoma patients.

Background: Ideal dosing for the preservative-free (PF) tafluprost/timolol fixed combination (TTFC) remains to be elucidated. Research design and methods: This study was a prospective, observer-masked, placebo-controlled, crossover, comparison in 42 consecutive open-angle glaucoma patients whose intraocular pressure (IOP) was insufficiently controlled with preserved latanoprost monotherapy (mean 24-h IOP >20 mmHg). Patients were randomized to either morning (08:00) or evening (20:00) PF TTFC for 3 months and then crossed over. After each treatment period, patients underwent habitual 24-h IOP monitoring with Goldmann tonometry in the sitting position (at 10:00, 14:00, 18:00, and 22:00) and Perkins tonometry in the supine position (at 02:00 and 06:00). Results: Mean 24-h IOP on latanoprost was 22.2±3.9 mmHg. Both PF TTFC dosing regimens obtained greater reduction in mean 24-h, daytime, nighttime, and peak 24-h IOP (P < 0.001). Evening dosing provided tighter 24-h IOP fluctuation versus latanoprost (P < 0.001). Evening dosing was superior to morning dosing at four time points (P < 0.01), for the mean daytime IOP (P < 0.001) and mean 24-h IOP fluctuation (P < 0.001). Hyperemia was more common with preserved latanoprost (21.4 vs. 7.1%; P = 0.031). Patients (n = 19; 45%) preferred evening dosing. Conclusions: PF TTFC provided greater 24-h IOP control and less hyperemia compared with preserved latanoprost. Evening administration of this novel medication offered superior 24-h efficacy. Trial registration: Clinicaltrials.gov (NCT03612817).

Prostaglandin (PTG) E and F receptors in the porcine corpus luteum; effect of tumor necrosis factor-α.

The porcine corpus luteum (CL) is NOT sensitive to the luteolytic effects of PGF-2α until days 12-13 of cycle. The control of "luteolytic sensitivity" (LS) of the pig CL to PGF-2α is unknown, but it is temporally associated with macrophage infiltration into the CL. Since macrophages are the predominant source of TNF-α in the porcine CL, in other studies we examined the effects of TNF-α on porcine luteal cells in culture and showed that TNF-α induces LS in vitro. In Experiment 1 of this study possible mechanisms involved in the control of LS were examined, and involved measurement of the protein levels of PTGER2/EP-2, and PTGER3/EP-3 in porcine CL collected before (days 7-10), versus after (day 13), the onset of the LS. In Experiment 2, an examination of potential mechanisms involved in the control of LS by TNF-α, was carried out in which the effects of TNF-α on mRNA and protein expression of EP-2, EP-3 and FP in cultured luteal cells, were examined. The results of Experiment 1 showed that PTGER-3/EP-3 (but not PTGER-2/EP-2) levels decreased in porcine CLs after (day 13) compared to before (day 7-10) LS. In Experiment 2, the data obtained showed that TNF-α decreased PTGER-3/EP-3 and increased PTGFR/FP protein (in EARLY stage CL). In conclusion, these studies suggest a role for PTGER-3/EP-3 in the acquisition of LS, and support the hypothesis that TNF-α from CL macrophages plays a critical role in the control of LS in the porcine CL, by increasing PTGFR/FP, and decreasing PTGER-3/EP-3 protein.

Ocular surface status in glaucoma and ocular hypertension patients with existing corneal disorders switched from latanoprost 0.005% to tafluprost 0.0015%: comparison of two prostaglandin analogues with different concentrations of benzalkonium chloride.

IMPORTANCE: Glaucoma treatment has often been associated with adverse side-effects from preservatives that are included in the used eye drops. BACKGROUND: To evaluate changes in the ocular surface and the presence of prostaglandin-induced corneal disorders after being switched from latanoprost 0.005% to low preservative tafluprost 0.0015% ophthalmic solution. DESIGN: Single centre, prospective study. PARTICIPANTS: Patients with primary open-angle glaucoma or ocular hypertension that had received treatment with once daily latanoprost 0.005% ophthalmic solution for control of intraocular pressure (IOP) for 3 months, with a score of above 1 on the National Eye Institute (NEI) ocular surface staining scale. METHODS: Following the ≥3 month latanoprost treatment period, patients were switched to once daily low preservative tafluprost 0.0015% ophthalmic solution. Patients were followed for a minimum of 3 months. MAIN OUTCOME MEASURES: Ocular surface changes were assessed by fluorescein staining score (NEI scale). Additional evaluations included tear break-up time, hyperaemia score, subjective symptoms, changes in intraocular pressure and presence of adverse reactions. RESULTS: Out of 59 patients enrolled, 51 were included in the final analysis. Fluorescein staining scores at baseline, prior to treatment switch, were 6.9 ± 3.1 and 3.3 ± 2.7 at the end of the study period (change in scores was -3.6 ± 2.2 [P < 0.001]). At last follow-up, significant improvements were observed in tear break-up time, hyperaemia score and subjective symptoms (all P < 0.05). CONCLUSIONS AND RELEVANCE: The clinical signs of ocular surface disease and subjective symptoms of dry eyes improved following the switch to low preservative tafluprost and demonstrated comparable IOP lowering effectiveness.

Effect of changing from preserved prostaglandins to preservative-free tafluprost in patients with glaucoma on tear film thickness.

PURPOSE: Long-term glaucoma therapy with preservative-containing eye drops may impact ocular surface health. This study was performed to investigate whether a switch from preserved topical prostaglandin therapy to preservative-free tafluprost therapy improves precorneal tear film thickness in patients with glaucoma or ocular hypertension. METHODS: A total of 30 patients who were under topical preservative-containing prostaglandin monotherapy for at least 6 months were included. Patients were then switched from preserved prostaglandin therapy to unpreserved tafluprost drops once daily. Tear film thickness was measured at baseline and 4 and 12 weeks after therapy change with an ultrahigh-resolution optical coherence tomography system. Furthermore, clinical measures of ocular surface disease were determined and symptoms were assessed using the Dry Eye-Related Quality-of-Life Score. RESULTS: After switching to unpreserved tafluprost, tear film thickness significantly increased from 4.7 ± 0.5 to 5.0 ± 0.6 µm 4 weeks after therapy change and still tended to be increased after 12 weeks (4.8 ± 0.7 µm). Breakup time significantly increased from 5.1 ± 2.3 to 7.2 ± 3.4 s and to 10.1 ± 3.6 s after therapy change. In addition, a significant decrease in corneal staining score from 1.8 ± 0.7 to 1.4 ± 0.8 after 4 weeks and to 0.7 ± 0.7 after 12 weeks treatment was observed. Switching to preservative-free drops reduced Dry Eye-Related Quality-of-Life Score from 11.4 ± 11.0 to 5.7 ± 6.4 and to 4.7 ± 7.5. CONCLUSION: Our data show that switching to preservative-free tafluprost leads to an increase in tear film thickness, breakup time, and an improvement of Dry Eye-Related Quality-of-Life Score. Our results therefore indicate that a switch to unpreserved tafluprost is beneficial for ocular surface health in patients under long-term preserved prostaglandin eye drops.

Eye Drop Dispenser Type and Medication Possession Ratio in Patients With Glaucoma: Single-Use Containers Versus Multiple-Use Bottles.

PURPOSE: To determine whether the consumption of topical glaucoma medication is influenced by the type of eye drop dispenser. DESIGN: Retrospective cohort study. METHODS: We examined 366 patients with open-angle glaucoma or ocular hypertension who were bilaterally treated with 0.0015% tafluprost or 2% dorzolamide/0.5% timolol fixed combination (DTFC). The patients were grouped by the type of dispenser and content of eye drops used: (1) tafluprost in bottles (T-Bottle group); (2) tafluprost in unit-dose pipettes (T-Unit group); (3) DTFC in bottles (C-Bottle group); and (4) DTFC in unit-dose pipettes (C-Unit group). We evaluated the medication possession ratio (MPR) among groups, and factors associated with over-consumption (MPR > 1.2) or under-consumption (MPR < 0.8) in multinomial logistic regression. RESULTS: The mean MPR was 1.49 (range, 0.69-2.91) in the T-Bottle group, 0.91 (range, 0.32-1.27) in the T-Unit group, 1.25 (range, 0.51-2.60) in the C-Bottle group, and 0.96 (range, 0.36-1.60) in the C-Unit group. The Bottle groups demonstrated higher mean values and wider ranges of MPR compared to the Unit groups. The MPR interval at which the largest number of patients were found was 1.0-1.4 in the Bottle groups and 0.8-1.2 in the Unit groups. Bottle-type dispenser (odds ratio [OR] 64.02), tafluprost medication (OR 2.84), and older age (OR 1.03) were associated with over-consumption, whereas no factor was correlated with under-consumption. CONCLUSIONS: The type of eye drop dispenser affects the consumption of glaucoma medication. Physicians should consider the type of eye drop dispenser when assessing glaucoma medication adherence.

Long term safety and tolerability of Tafluprost 0.0015% vs Timolol 0.1% preservative-free in ocular hypertensive and in primary open-angle glaucoma patients: a cross sectional study.

BACKGROUND: The effects of preservatives of antiglaucoma medications on corneal surface and tear function have been widely shown in literature; it's not the same as regards the active compounds themselves. The purpose of our study was to compare Ocular Surface Disease (OSD) signs and symptoms of Tafluprost 0.0015% versus preservative free (PF) Timolol 0.1% eyedrops in ocular hypertensive (OH) and in primary open-angle glaucoma (POAG) patients. METHODS: A cross-sectional study included patients in monotherapy for at least 36 months with Tafluprost 0.0015% (27) or PF Timolol 0.1% (24) and 20 healthy age and sex-matched volunteers. All subjects underwent clinical tests (Schirmer I and break-up time), in vivo confocal microscopy (IVCM) and were surveyed using Ocular Surface Disease Index (OSDI) and Glaucoma Symptoms Scale (GSS) questionnaires. The groups were compared with ANOVA, Kruskal-Wallis test, t-test, Mann-Whitney test and Bonferroni's adjustment of p-values. RESULTS: No significant differences were found in questionnaires scores, clinical tests, IVCM variables between therapy groups. Tafluprost 0.0015% group showed significantly higher OSDI score, basal epithelial cells density, stromal reflectivity, sub-basal nerves tortuosity (p = 0.0000, 0.037, 0.006, 0.0000) and less GSS score, number of sub-basal nerves (p = 0.0000, 0.037) than controls but similar clinical tests results (p > 0.05). PF Timolol group had significantly higher OSDI score, basal epithelial cells density, stromal reflectivity and sub-basal nerve tortuosity (p = 0.000, 0.014, 0.008, 0.002), less GSS score, BUT and number of sub-basal nerves (p = 0.0000, 0.026, 0.003) than controls. CONCLUSIONS: Compared to PF Timolol 0.1%, Tafluprost 0.0015% showed similar safety with regards to tear function and corneal status and a similar tolerability profile. Both therapy groups show some alterations in corneal microstructure but no side effects on tear function except for an increased tear instability in PF Timolol 0.1% group. Ophtalmologists should be aware that even PF formulations may lead to a mild ocular surface impairment.

Retinal Blood Flow Velocity Change in Parafoveal Capillary after Topical Tafluprost Treatment in Eyes with Primary Open-angle Glaucoma.

Although ocular circulation at the retina and optic disc is known to be associated with the pathology of glaucoma, direct measurement of blood flow velocity has been difficult to obtain. This prospective observational study enrolled 11 consecutive patients with treatment-naïve primary open-angle glaucoma (POAG) and 11 healthy subjects, and the effects of topical tafluprost treatment on ocular circulation were examined at baseline and at 1, 4, and 12 weeks after initiating treatment with topical tafluprost on POAG patients using multiple modalities, which include adaptive optics scanning laser ophthalmoscopy (AOSLO). Baseline mean intraocular pressure (IOP) was significantly higher and mean parafoveal blood flow velocity (pBFV) was significantly lower in POAG eyes than in healthy eyes. Mean IOP was significantly decreased (1 week, -19.1%; 4 weeks, -17.7%; and 12 weeks, -23.5%; all P < 0.001) and mean pBFV was significantly increased from the baseline at all follow-up periods after initiating treatment (1 week, 14.9%, P = 0.007; 4 weeks, 21.3%, P < 0.001; and 12 weeks, 14.3%, P = 0.002). These results reveal that tafluprost may not only lower IOP but may also improve retinal circulation in POAG eyes and AOSLO may be useful to evaluate retinal circulatory change after treatment.

Effects of pre-surgical administration of prostaglandin analogs on the outcome of trabeculectomy.

For primary open angle glaucoma (POAG), laser treatment or surgery is used when the target intraocular pressure (IOP) cannot be achieved by pharmacological agents, such as prostaglandin (PG) analogs; these drugs also have varied effects. We retrospectively reviewed the medical records of 74 POAG patients (74 eyes) whose IOP was inadequately controlled by PG analogs (bimatoprost [13 eyes], latanoprost [34 eyes], tafluprost [11 eyes], and travoprost [16 eyes]) and underwent primary trabeculectomy. The proportion of patients with no recurrent IOP elevation within 24 months post-trabeculectomy was significantly (P < 0.001) lower in the bimatoprost group (31.3%) than in the latanoprost (83.2%), tafluprost (45.5%), or travoprost groups (65.6%). Deepening of the upper eyelid sulcus (DUES) was observed before trabeculectomy in 18 of 74 eyes (24.3%) treated with bimatoprost (9 eyes; 50.0%), latanoprost (3 eyes; 16.7%), tafluprost (1 eye; 5.5%) and travoprost (5 eyes; 27.8%). The proportion of patients with no recurrent IOP elevation up to 24 months post-trabeculectomy was significantly (P < 0.0001) lower in the DUES(+) group (34.7%) than in the DUES(-) group (74.3%). Multivariate stepwise logistic regression analysis, with no recurrent IOP elevation used as dependent variable, and bimatoprost, latanoprost, travoprost, tafluprost, ß-blocker, carbonic anhydrase inhibitor, brimonidine, gender, age, preoperative IOP, mean deviation, duration of PG analog use before surgery, and the number of ophthalmic solutions used as independent variables, identified only bimatoprost as a significant independent factor (P = 0.0368). Thus, the outcome of trabeculectomy varied depending on the PG analog used preoperatively, and bimatoprost use was associated with a high risk of recurrent IOP elevation up to 2 years post-trabeculectomy. This may indicate that the incidence of DUES differed with the PG analog used. Patients with glaucoma who are treated with bimatoprost should be monitored for DUES, and when these patients undergo trabeculectomy, the postoperative course of IOP should be followed carefully.

Prospective Observational Post-Marketing Study of Tafluprost for Glaucoma and Ocular Hypertension: Effectiveness and Treatment Persistence.

INTRODUCTION: The aim of this study was to investigate the long-term intraocular pressure (IOP)-lowering effect and safety of tafluprost, a prostaglandin analogue, in actual clinical practice and to determine persistency of tafluprost as an indicator of its benefit-risk balance. METHODS: This was a large-scale, post-marketing, multicenter, non-interventional, open-label, long-term study. Patients with glaucoma or ocular hypertension who initiated tafluprost treatment were registered and prospectively observed over a 2-year period in the real-world setting in Japan. Long-term IOP and safety data were collected. RESULTS: Of the 4502 patients registered from 553 medical institutions, 4265 patients were analyzed. The majority of patients had normal-tension glaucoma (44.4%) and primary open-angle glaucoma (37.8%), and patients with ocular hypertension constituted 7.0%. Treatment patterns with tafluprost during the study period were as follows: naïve monotherapy (48.1%), switching monotherapy (18.4%), and concomitant therapy (33.5%). In all patients analyzed, mean IOP was significantly reduced from 18.6 ± 5.9 mmHg (month 0) to 15 mmHg or below throughout the 2-year observation period after initiation of tafluprost. Significant IOP-lowering effects were shown in various treatment patterns and disease types. Adverse reactions were observed in 795 patients (18.64%). Major adverse reactions included eyelid pigmentation, ocular hyperemia, eyelash changes, eyelid hypertrichosis, and iris hyperpigmentation. Kaplan-Meier curves showed that 84.6% and 76.1% of patients were persistent on tafluprost for 1 and 2 years, respectively, when discontinuation due to insufficient efficacy or adverse events was defined as a treatment failure event. Furthermore, among treatment-naïve patients (n = 2304), the persistency rates on tafluprost monotherapy were 77.0% for 1 year and 67.0% for 2 years. CONCLUSION: Tafluprost showed significant long-term IOP-lowering effects regardless of treatment patterns or diagnosis, with minimum safety concerns in the actual clinical practice. The observed treatment persistence suggests that tafluprost can be used long term owing to its benefit-risk profile. FUNDING: Santen Pharmaceutical Co., Ltd., Osaka, Japan.

Efficacy and tolerability of preservative-free 0.0015% tafluprost in glaucoma patients: a prospective crossover study.

BACKGROUND: The aim of this work is to evaluate efficacy and tolerability of preservative containing 0.0015% tafluprost and preservative-free 0.0015% tafluprost using a prospective crossover study. METHODS: Primary open angle glaucoma (POAG) and normotensive glaucoma (NTG) patients were randomized enrolled. Group 1 ("NPT to PT") patients used preservative-free 0.0015% tafluprost (NPT) for 6 months and then changed to preservative containing 0.0015% tafluprost(PT) for 6 months. Group 2 ("PT to NPT") patients used preservative containing 0.0015% tafluprost for 6 months and changed to preservative-free 0.0015% tafluprost for 6 months. At 1, 3, 6, 7, 9, and 12 months, we measured intraocular pressure for efficacy and graded corneal erosion, tear break-up time (TBUT), and subjective discomfort. RESULTS: A total of 20 patients and 20 eyes were enrolled. In Group 1 and 2, intraocular pressure was well controlled to approximately 14 mmHg (9.38-18.46% decrease). Generally, subjective satisfaction was improved after changing from PT to NPT (p = 0.03) and TBUT using PT was numerically inferior to that using NPT (p = 0.06) but not when changing from NPT to PT. CONCLUSION: Both preservative containing and preservative-free 0.0015% tafluprost reduced intraocular pressure significantly. In addition, changing medication from PT to NPT might improve subjective satisfaction and tear break up time. TRIAL REGISTRATION: The trial registration number is NCT 03104621 (Apr/1/2017). Retrospectively registered.

24-Hour Efficacy and Ocular Surface Health with Preservative-Free Tafluprost Alone and in Conjunction with Preservative-Free Dorzolamide/Timolol Fixed Combination in Open-Angle Glaucoma Patients Insufficiently Controlled with Preserved Latanoprost Monotherapy.

INTRODUCTION: The aim of the present study was to evaluate the 24-h efficacy, tolerability, and ocular surface health with preservative-free (PF) tafluprost and a PF triple drug regimen comprising tafluprost and dorzolamide/timolol fixed combination (DTFC) in open-angle glaucoma patients who were insufficiently controlled with preserved branded or generic latanoprost monotherapy and who exhibited signs or symptoms of ocular surface disease (OSD). METHODS: Prospective, observer-masked, crossover, comparison. Eligible consecutive open-angle glaucoma patients were randomized to either PF tafluprost or the triple PF regimen for 3 months. They were then crossed over to the opposite therapy for another 3 months. At the end of the latanoprost run-in period and after each PF treatment period, patients underwent habitual 24-h intraocular pressure (IOP) monitoring with Goldmann tonometry in the sitting position (at 10:00, 14:00, 18:00, and 22:00) and Perkins tonometry in the supine position (at 02:00 and 06:00). Tolerability and selected ocular surface parameters were evaluated at baseline and the end of each treatment period. RESULTS: Forty-three open-angle glaucoma patients completed the trial. Mean 24-h IOP on preserved latanoprost was 22.2 ± 3.9 mmHg. Compared with latanoprost monotherapy, PF tafluprost obtained a greater reduction in mean, peak, and fluctuation of 24-h IOP including the 02:00 and 06:00 time points (P < 0.05). With the exception of 24-h fluctuation, the triple PF regimen provided significantly lower IOP parameters than latanoprost or PF tafluprost (P < 0.001). Finally, PF tafluprost therapy displayed significantly improved tear film break-up times (6.7 vs 6.0 s), corneal staining (1.3 vs 2.2), and Schirmer I test results (9.1 vs 8.2 mm) compared with the preserved latanoprost baseline (all P < 0.01). The triple PF regimen demonstrated similar tear film break-up times (6.1 vs 6.0 s) and Schirmer I test results (8.2 vs 8.2 mm) to latanoprost, but revealed a significant improvement in the corneal stain test (1.7 vs 2.2; P < 0.001). CONCLUSIONS: In this trial PF tafluprost therapy provided statistically greater 24-h efficacy and improved tolerability compared with preserved latanoprost. The combination of PF tafluprost and PF dorzolamide/timolol fixed combination was statistically and clinically more efficacious than both monotherapies and demonstrated similar ocular surface characteristics to preserved latanoprost monotherapy. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02802137). FUNDING: Santen.

Impact of prostaglandin glaucoma drops on platelet-activating factor action: an in vitro study.

AIM: The aim of this study was to investigate the effect of different prostaglandin analogs on platelet-activating factor (PAF) levels. METHODS: Three prostaglandin analogs were selected: bimatoprost 0.3 mg/mL, latanoprost 50 µg/mL, and tafluprost 15 µg/mL. Each drug sample was tested for its ability to cause platelet aggregation, which was measured as PAF-induced aggregation, before and after the addition of various concentrations of the examined sample, creating a linear curve of percentage inhibition (ranging from 0% to 100%) versus different concentrations of the sample. The concentration of the sample that inhibited 50% PAF-induced aggregation was calculated based on this curve, and this value was defined as IC50. In addition, the effect of eye drops on PAF metabolism was examined, through an in vitro analysis on PAF basic metabolic enzymes (PAF-cholinephosphotransferase, PAF-acetyl-CoA:1-O-alkyl-sn-glycero-3-phosphocholine acetyltransferase, and PAF-acetylhydrolase). RESULTS: The IC50 values for Lumigan UD® (bimatoprost 0.3 mg/mL), Monoprost® (latanoprost 50 µg/mL), and Saflutan (tafluprost 15 µg/mL) were 8.7, 0.28, and 1.4 µg/mL, respectively. DISCUSSION: All three prostaglandin analogs suspended PAF, but bimatoprost induced the most potent inhibition, compared to tafluprost and to the weak effect of latanoprost.