Efficacy of preserved Tafluprost 0.0015% in lowering intraocular pressure.

OBJECTIVE: To investigate the intraocular pressure (IOP) lowering effect of topical preserved tafluprost 0.0015% in a tertiary hospital setting in India. METHODS: This is a retrospective chart review of patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT) attending regular outpatient visits in December 2019 and January 2021, and treated with topical preserved tafluprost 0.0015%. Based on their medication history, patients were divided into two groups, the "treatment naïve" group and the "switched" group, which included patients switched to tafluprost monotherapy after treatment with at least one prior drug. RESULTS: The mean IOP of the study population reduced significantly from baseline level by 20.6% and 25.5% at 1 month and 3 months after preserved tafluprost 0.0015% treatment (P < 0.001 for both). The mean IOP in patients with only OHT reduced significantly from baseline level by 21% and 26% at 1 month and 3 months after preserved tafluprost 0.0015% treatment (P < 0.001 for both). The mean IOP in patients with POAG reduced significantly from baseline level by 19% and 24% at 1 month and 3 months after preserved tafluprost 0.0015% treatment (P < 0.001 for both). The baseline IOP ± SD in POAG treatment naïve patients was 25.3 ± 0.3 mmHg, which reduced significantly by 24% and 28% at 1 month and 3 months after preserved tafluprost 0.0015% treatment (P < 0.001 for both). The baseline IOP ± SD in POAG switched patients was 24.3 ± 0.1 mmHg, which reduced significantly by 18% and 22% at 1 month and 3 months after preserved tafluprost 0.0015% treatment (P < 0.001 for both). In the POAG switch group, the percent reduction in IOP at 3 months after preserved tafluprost 0.0015% treatment was 23% with timolol as first line, 22% with bimatoprost as first line, 20% with latanoprost as first line, and 19% with travoprost as first line (P < 0.001 for all). CONCLUSIONS: We show significant IOP reduction with preserved tafluprost 0.0015% in a real-world setting. As first-line monotherapy in patients with OHT and in POAG-naïve patients, preserved tafluprost 0.0015% significantly reduced IOP at 3 months. Even as second-line therapy in nonresponders (POAG-Switched) to various drugs (same class [PGAs] versus different class), treatment with preserved tafluprost 0.0015% resulted in significant IOP reduction at 3 months.

The evaluation of the effect of tafluprost on the intraocular pressure of healthy male guinea pigs under different light-and-darkness regimes.

BACKGROUND: Ocular hypertension is one of the most underdiagnosed ocular abnormalities among guinea pigs around the world. OBJECTIVES: The current study investigates the effect of 0.0015% preservative-free tafluprost ophthalmic solution (Zioptan) on the intraocular pressure of 16 healthy male guinea pigs (Cavia porcellus) under different light/darkness regimes. METHODS: All guinea pigs received a single drop of tafluprost at 5:30 in the right eye, whereas the contralateral eyes served as control to receive a placebo. Then, the animals were randomly divided into two groups; group A was exposed to light, whereas group B was placed in darkness from 5:30 to 18:00. Rebound tonometry (TonoVet) was instrumented to measure IOP values at 5:30 (baseline), 6:00, 7:00, 8:00, 9:00 and then every 3 h until 18:00. RESULTS: The maximum IOP reduction associated with tafluprost was observed at 6:00 by -1.4 ± 1.1 mmHg (p-value = 0.026) and -2.5 ± 1.2 mmHg (p-value = 0.011) in group A and B, respectively (repeated measure ANOVA test). There was a significant difference between the mean right and left eye IOP values in both groups at 5:30, 6:00, 7:00 and 8:00 (p-value <0.05), which was greater in amount in group B compared to group A due to the effect of darkness on IOP reduction. CONCLUSIONS: It is suggested that the variations of IOP in different light/dark conditions be taken into consideration when applying ocular hypotensive agents on guinea pigs' eyes.

The mechanism of ginger and its processed products in the treatment of estradiol valerate coupled with oxytocin-induced dysmenorrhea in mice via regulating the TRP ion channel-mediated ERK1/2/NF-κB signaling pathway.

Ginger (Rhizoma zingiberis, RZ) has been used as a food, spice, supplement, flavoring agent, and as an edible herbal medicine. It is characterized by its pungency and aroma, and is rich in nutrients with remarkable pharmacological effects. It is used in traditional medicine clinics to treat diseases and symptoms, such as colds, headache, and primary dysmenorrhea (PD). In China, a variety of processed products of RZ are used as herbal medicines, such as baked ginger (BG) or ginger charcoal (GC) to treat different diseases and symptoms. However, the molecular mechanism of the therapeutic effect of RZ and its processed products (RZPPs, including BG or GC) against PD has not been well characterized. Moreover, whether the transient receptor potential (TRP) ion channels are involved in this process is not clear. In the present study, UHPLC-Q-TOF MS was adopted to analyse the differential quality markers (DQMs) between RZ and RZPPs. In addition, differential metabolomics (DMs) was acquired between RZ- and RZPPs-treated estradiol valerate coupled with an oxytocin-induced PD mouse uterus using untargeted metabolomics (UM). A correlation analysis between DQMs and DMs was also conducted. Benzenoids, lipids, and lipid-like molecules were the main DQMs between RZ and RZPPs. RZ and RZPPs were found to improve the pathological status of the uterus of a PD mouse, with significantly decreased serum levels of E2, PGF2α, TXB2 and remarkably increased levels of PROG and 6-keto-PGF1α. Moreover, RZ and RZPPs alleviated PD in mice via regulating the TRP ion channel-mediated ERK1/2/NF-κB signaling pathway. Our results indicate that the therapeutic effect of RZ and RZPPs against PD may be mediated by regulating the TRP ion channel-mediated ERK1/2/NF-κB signaling pathway, and provide a reference for the development of new dietary supplements or medicines.

[Anti-inflammatory and hemostatic effects of total extract, saponins, and flavonoids of Clinopodium chinense in female rats with abnormal uterine bleeding and mechanism].

This study aims to explore the anti-inflammatory and hemostatic effects of the total extract of Clinopodium chinense(TEC), total saponins of C. chinense(TSC), and total flavonoids of C. chinense(TFC) in female rats with abnormal uterine bleeding(AUB), and the possible mechanism. Mifepristone(i.g., 12.4 mg·kg~(-1)) and misoprostol(i.g., 130 µg·kg~(-1)) were used to induce AUB in SD female rats conceiving on the same day. Then the AUB rats were randomized into model group, TEC group, TSC group, TFC group, Yimucao Granules(LG) group, and estradiol valerate(EV) group, with 8 rats in each group. Another 8 non-pregnant female rats were selected as normal group. During the experiment, each group was given the corresponding drug by gavage once a day for 7 days. After the administration, blood and uterine tissue were collected. The uterine bleeding volume was measured by ultraviolet spectrophotometry and the pathological changes of endometrium were observed based on hematoxylin-eosin(HE) staining. In addition, the microvessel density of endometrium was determined by immunohistochemistry, and the content of thromboxane B2(TXB2), 6-keto-PGF_(1α), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α) in plasma and levels of lutenizing hormone(LH), follicle stimulating hormone(FSH), estradiol(E_2), and progesterone in serum were detected by enzyme-linked immunosorbent assay(ELISA). The mRNA and protein expression of estrogenreceptor α(ERα), progesterone receptor(PR), matrix metalloproteinase(MMP)-2, MMP-9, and vascular endothelial growth factor(VEGF) in uterine tissue was determined by Western blot. Compared with the model group, TEC, TSC, and TFC can reduce uterine bleeding volume, alleviate the pathological damage of endometrium, and increase the microvessel density in endometrium. Moreover, TEC and TSC can significantly raise plasma TXB2 level and ratio of TXB2 to 6-keto-PGF_(1α), and TEC and TFC can significantly reduce the levels of IL-6 and TNF-α. In addition, TEC significantly elevated serum progesterone level and TFC significantly increased serum levels of E_2, FSH, and LH. TSC can significantly raise serum progesterone and FSH levels. In addition, TEC can significantly down-regulate the protein expression of PR, MMP-2, and VEGF and TSC significantly reduced the expression of MMP-9. TFC significantly decreased the expression of PR, MMP-9, and VEGF, and up-regulated the expression of ERα. In conclusion, TEC, TSC, and TFC all show therapeutic effects on AUB, particularly TEC. TSC exerts the effects by enhancing the coagulation function and promoting endometrial repair, and TFC by regulating estrogen levels and reducing inflammatory response. This study reveals the mechanism of C. chinense against AUB and also explains the holistic characteristics of Chinese medicine.

Effects of 0.0015% preservative-free tafluprost on the equine eye.

OBJECTIVE: The purpose of this study was to determine the effects and potential side effects of topical preservative-free (PF) tafluprost 0.0015% in ophthalmologically normal horses. ANIMALS: Five adult grade horses. PROCEDURES: One of the eyes of each horse was randomly chosen as the "treatment" eye, and consequently, the contralateral eye served as the "control." A single dose of PF tafluprost 0.0015% (0.2 mL) was instilled in the treated eye of each horse. Intraocular pressure (IOP), Schirmer's tear test (STT) levels of each eye, and an ophthalmic examination were performed at T0 (baseline), T30, T120, T24 h, and T48 h. RESULTS: The mean IOP values of the treated eyes at baseline (T0), T30, T120, T24 h, and T48 h were 25.4 ± 4.8 mmHg, 21.2 ± 1.92 mmHg, 15.20 ± 2.48 mmHg, 18.40 ± 1.51 mmHg, and 24.60 ± 1.94 mmHg, respectively. Significant differences were observed between the mean baseline IOP level and the T120 and T24 h time points (p = .001 and p = .009). The mean STT levels at each time point showed insignificant fluctuations during the study (p = .140). Adverse effects such as chemosis and episcleral injection were observed 30 min after the instillation of tafluprost 0.0015% (T30). Blepharospasm and conjunctival hyperemia were observed 120 min (T120) after the administration of the medication. CONCLUSION AND CLINICAL RELEVANCE: Tafluprost 0.0015% showed potential in reducing IOP, but due to its local side effects, it is not a good candidate for management of glaucoma in horses. Tafluprost did not notably affect STT.

Progesterone-responsive vaginal leiomyoma and hyperprogesteronemia due to ovarian luteoma in an older bitch.

BACKGROUND: This is the first report about a vaginal leiomyoma concomitant with an ovarian luteoma in a bitch. CASE PRESENTATION: A 11-year-old intact female Labrador retriever was referred because of anuria, constipation and protrusion of a vaginal mass through the vulvar commissure. The bitch had high serum progesterone concentration (4.94 ng/ml). Because of the possibility of progesterone responsiveness causing further increase of the vaginal mass and since the bitch was a poor surgical candidate a 10 mg/kg aglepristone treatment was started SC on referral day 1. A computerized tomography showed a 12.7 × 6.5 × 8.3 cm mass causing urethral and rectal compression, ureteral dilation and hydronephrosis. A vaginal leiomyoma was diagnosed on histology. As serum progesterone concentration kept increasing despite aglepristone treatment, a 0.02 ng/mL twice daily IM alfaprostol treatment was started on day 18. As neither treatment showed remission of clinical signs or luteolysis, ovariohysterectomy was performed on referral day 35. Multiple corpora lutea were found on both ovaries. On histology a luteoma was diagnosed on the left ovary. P4 levels were undetectable 7 days after surgery. Recovery was uneventful and 12 weeks after surgery tomography showed a reduction of 86.7% of the vaginal mass. The bitch has been in good health and able to urinate without any complication ever since. CONCLUSIONS: This case demonstrates the importance of identifying progesterone related conditions as well as the importance of judiciously using a combined medical and surgical approach.

Effectiveness of Blepharoptosis Surgery in Patients With Deepening of the Upper Eyelid Sulcus.

The purpose of this retrospective study was to evaluate the effectiveness of blepharoptosis surgery in patients with deepening of the upper eyelid sulcus (DUES). This case series included 10 consecutive patients (19 eyes) with DUES associated with use of a prostaglandin analog for glaucoma. Patients who had used bimatoprost and developed DUES were changed to an alternative prostaglandin analog and observed for ≥3 months. If there was no improvement, they underwent levator resection for blepharoptosis and were followed up for ≥6 months postoperatively. Improvement in margin reflex distance-1 and surgical complications was evaluated. After discontinuation of bimatoprost in 3 cases (6 eyes), mild subjective and objective improvement in DUES was seen in 2 cases (4 eyes) but without improvement in blepharoptosis. The prostaglandin analog used before surgery was travoprost in 4 eyes (21.0%), tafluprost in 7 eyes (36.9%; including 4 eyes switched from bimatoprost), and latanoprost in 8 eyes (42.1%; including 2 eyes switched from bimatoprost). The mean margin reflex distance-1 value was 1.11 ±â€Š0.96 mm before surgery and 3.72 ±â€Š0.81 mm at the final postoperative follow-up; the difference was significant (P = 3.32 × -10). There were no intraoperative or postoperative complications. Levator resection is a useful and safe procedure for blepharoptosis with DUES.

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.

Changes in Prostaglandin-associated Periorbital Syndrome After Switch from Conventional Prostaglandin F2α Treatment to Omidenepag Isopropyl in 11 Consecutive Patients.

PURPOSE: We evaluated the recovery of patients with PAPS for whom the treatment regimen switched from conventional prostaglandin F2α analogues to a new selective prostaglandin-EP2 agonist: omidenepag isopropyl. PATIENTS AND METHODS: From November 2018 to July 2019, we prospectively evaluated 11 patients who had been using conventional PGF2α drugs. Digital photographs of the patients were taken before the start of omidenepag isopropyl therapy and ~3 and 6 months after. Three independent observers used the photographs to judged recovery according to the 5 signs of PAPS: deepening of the upper eyelid sulcus (DUES), flattening of the lower eyelid bags, upper eyelid ptosis, ciliary hypertrichosis, and periorbital skin hyperpigmentation. RESULTS: The mean age of patients was 61, and 7 patients were female. The original PGF2α drugs were bimatoprost, latanoprost, travoprost, and tafluprost. The mean duration of PGF2α treatment was 65 months. PAPS signs were evaluated in 10 patients after 3 months and in all 11 patients after 6 months: After 3 and 6 months, DUES improved in 3 and 3 patients, respectively; flattening of the lower eyelid bags improved in 1 and 2 patients, respectively; upper eyelid ptosis did not improve in any patients; ciliary hypertrichosis improved in 0 and 2 patients, respectively; and eyelid pigmentation improved in 2 and 8 patients, respectively. The 3 patients who showed improvement in DUES at 6 months had all previously used bimatoprost. CONCLUSIONS: Some PAPS signs improved after patients started taking omidenepag isopropyl. Our findings will be useful for patients taking antiglaucoma eye drops.

Effect of Topical Prostaglandin F2α Analogs on Selected Oxidative Stress Parameters in the Tear Film.

Background and Objectives: Topically administered antiglaucoma medications, especially those containing benzalkonium chloride (BAC), may cause local adverse effects and compromise ocular surface. The aim of the study was to assess the effect of topical prostaglandin F2α analogs (PGAs): preservative-free latanoprost, BAC-preserved latanoprost, preservative-free tafluprost, and BAC-preserved bimatoprost, on selected oxidative stress parameters in the tear film. Materials and Methods: The patients were divided into five groups: group C (n = 25) control group-subjects who did not use topical antiglaucoma medications, group L (n = 22)-patients using topical preservative-free latanoprost, group L+BAC (n = 25)-patients using topical BAC-preserved latanoprost, group T (n = 19)-patients using topical preservative-free tafluprost, and group B+BAC (n = 17)-patients using topical BAC-preserved bimatoprost. The oxidative stress markers in the tear film samples were evaluated: total protein (TP) concentration, advanced oxidation protein products (AOPP) content, total sulfhydryl (-SH) groups content, the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), as well as Total Oxidant Status (TOS), Total Antioxidant Response (TAR), and Oxidative Stress Index (OSI). Results: The TP concentrations in the groups L, L+BAC, and B+BAC were statistically significantly higher in comparison with group C. The SOD and CAT activities in the groups L+BAC and B+BAC were statistically significantly higher when compared to group C. As compared to group C, AOPP and TOS were statistically significantly higher in all the study groups. OSI was found to be statistically significantly higher in the groups L+BAC, T, and B+BAC in comparison with group C. Conclusion: Use of topical PGAs by the patients with ocular hypertension or primary open-angle glaucoma is associated with increased oxidative stress in the tear film which is additionally exacerbated by the presence of BAC in the formulation.

Meibomian gland dropout rate as a method to assess meibomian gland morphologic changes during use of preservative-containing or preservative-free topical prostaglandin analogues.

PURPOSE: To investigate the usefulness of meibomian gland (MG) dropout rate in the evaluation of MG morphological change associated with the use of prostaglandin for glaucoma treatment through the association between MG and the ocular surface parameters and medication duration and presence of preservative. METHODS: This cross-sectional study was conducted on 88 eyes of 88 patients who were diagnosed with glaucoma and used only Tafluprost as treatment. The patients were divided into four "user" groups: 1) 23 patients used preservative-free (PF) Tafluprost for 6 months; 2) 21 patients used preservative-containing (PC) Tafluprost for 6 months; 3) 23 patients used PF-Tafluprost for 24 months; 4) 21 patients used PC-Tafluprost for 24 months. Ocular surface parameters and the MG condition, including MG dropout rate and meiboscale, were evaluated. Multiple regression was used to identify associations. RESULTS: There were significant differences in age (p = 0.003), tear breakup time (p = 0.016), lid margin abnormality (p = 0.016), expressibility (p = 0.039), meiboscale (p<0.001), and MG dropout rate (p<0.001) among the 4 groups. MG dropout rate and meiboscale showed significant differences in all post hoc analyses, except for the comparison between the PF-Tafluprost and PC-Tafluprost 6-month user groups. Medication duration, preservative status, and meiboscale were significantly correlated with MG dropout rate (p<0.001, p = 0.024, p<0.001, respectively). In the 6-month user group, preservative status significantly correlated with MG dropout rate (p = 0.015). However, in the 24-month user group, meiboscale was the only parameter significantly associated with MG dropout rate (p<0.001). CONCLUSION: MG dropout rate in patients using Tafluprost showed a significant correlation with medication duration and preservative status. This result indicates MG dropout rate reflects MG morphologic change associated with prostaglandin.

Patient Preference-Based Comparative Effectiveness and Cost-Utility Analysis of the Prostamides for Open-Angle Glaucoma.

PURPOSE: To perform patient preference-based comparative effectiveness and cost-utility (cost-effectiveness) analyses to evaluate topical bimatoprost 0.01%, latanoprost 0.005%, travoprost 0.004%, tafluprost 0.0015%, and timolol 0.5% for the treatment of open-angle glaucoma (OAG). METHODS: Value-Based Medicine®, incremental cost-utility analysis, and average cost-utility analysis were performed using published systematic review and network meta-analyses with 3-month clinical data for a base case of OAG with an untreated intraocular pressure of 26 mm Hg. Visual acuity and visual field changes were converted to time tradeoff utility format. A 20-year model was undertaken; bilateral therapy was presumed; a national average Medicare Fee Schedule was used; and ophthalmic, third party insurer, and societal cost perspectives were utilized. Patient value outcomes (QALYs or quality-adjusted life-years) and costs were discounted at 3% annually. RESULTS: Bimatoprost conferred a mean 2.56 QALY gain (22.9% patient quality-of-life gain) for the average OAG patient, while latanoprost for the average OAG patient, while latanoprost conferred a 2.00 QALY gain (17.8% quality-of-life gain), tafluprost a 1.99 QALY gain (17.9% quality-of-life gain), travoprost a l.92 QALY gain (17.2% quality-of-life gain), and timolol a 1.42 QALY gain (12.8% quality-of-life gain). The ophthalmic cost-perspective, incremental cost-utility ratio of bimatoprost referent to travoprost was $6,034/QALY, to latanoprost was $27,973/QALY, and to timolol was $16,063/QALY. Bimatoprost dominated tafluprost, meaning that it conferred greater patient value for lesser cost than tafluprost. CONCLUSIONS: Topical bimatoprost delivers greater patient value than the other prostamides and topical timolol for the treatment of OAG. Bimatoprost is incrementally cost-effective referent to the other prostamides and timolol.

An in vivo confocal, prospective, masked, 36 months study on glaucoma patients medically treated with preservative-free or preserved monotherapy.

The aim of this study was to evaluate the in vivo effects at 3 years of preservative-free tafluprost on corneal health. It was a prospective, masked, study on consecutive patients with a new prescription of preservative-free (PF) tafluprost (naïve-N or switched-S, 44 and 14 patients), and preserved (P) bimatoprost 0.003% or travoprost 0.004% (P-group, 35 patients). A complete ophthalmic examination and an in vivo corneal confocal microscopy evaluation were performed at baseline and every 6 months for 3 years. Ninety-three patients were enrolled, clinical parameters were similar in the groups at baseline, apart from intraocular pressure (IOP) which was lower in the S-group (p = 0.012). Both at baseline and over time, confocal microscopy parameters had different trends. At baseline, keratocyte activation was similar in the three groups (p = 0.43) but over the next months naïve patients treated with PF-tafluprost presented a significant (p = 0.004) reduction in keratocyte activation. Sub-basal nerves tended to increase in patients switched to PF-tafluprost (p = 0.07) while were stable in the other two groups (p = 0.11 in PF and 0.40 in P group). Grade of tortuosity was stable over time in the three groups. Beading-like formations were stable over time for the P- and the PF-group, while significantly increased in the S-group (p = 0.027). Endothelial density values were statistically different at baseline (p = 0.007), they decreased both in PF-group and in S-group (p = 0.048 and 0.001, respectively), while increased in P-group (p = 0.006). Our study is the first to show that a PF-tafluprost formulation does not significantly alter the corneal structures as examined by confocal microscopy after 36 months of topical daily therapy, while improving corneal alterations due to chronic preserved therapies.

Discovery, characterization and clinical utility of prostaglandin agonists for the treatment of glaucoma.

Topical ophthalmic formulations of analogues of the endogenous arachidonic acid cyclooxygenase metabolite, PGF2α , are the standard of care treatment for the blinding disease glaucoma. These are the most potent and efficacious medical therapies for lowering intraocular pressure (IOP), the most important risk factor identified for disease progression. They have few side effects and offer the convenience of once-a-day dosing. It was initially believed that endogenous PGs raised IOP and caused substantial ocular surface adverse effects. However, carefully designed experiments demonstrated that esterification of the carboxylic acid afforded potent and efficacious topical ocular hypotensive activity. The final hurdle to be overcome was improvement of the side effect profile. A hypothesis was advanced that the IOP-lowering effect of PGF2α isopropyl ester was due to activation of its cognate PG-FP receptor, while side effects were largely due to promiscuous interaction with other PG receptors. This hypothesis was validated by modification of the ω chain (carbons 13-20) to a phenyl group. This provided the first marketed FP-class PG agonist analogue (FP-PGA) ocular hypotensive agent, latanoprost. Since the introduction of latanoprost into clinical medicine to lower and control IOP, a number of additional FP-PGAs have been discovered, characterized and marketed, including travoprost, tafluprost, unoprostone isopropyl ester and bimatoprost (an amide). LINKED ARTICLES: This article is part of a themed section on Eicosanoids 35 years from the 1982 Nobel: where are we now? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.8/issuetoc.

Patient stratification in clinical glaucoma trials using the individual tear proteome.

Glaucoma patients are prone to concomitant ocular surface diseases; however, switching from preserved to preservative-free medication can often alleviate these symptoms. The objective of this study was to examine how the adverse effects and tear proteome change for glaucoma patients (n = 28) during a 12-month drug switch from preserved latanoprost (Xalatan) to preservative-free tafluprost (Taflotan). We hypothesized that patient stratification could help identify novel recovery patterns in both tear proteomics and clinical data. In order to accomplish patient stratification, we implemented sequential window acquisition of all theoretical mass spectrometry (SWATH-MS) as a tool for quantitative analysis of individual tear protein profiles. During each visit (baseline and four follow-up visits), the patients' tears were sampled and the state of their ocular surface was evaluated clinically. Altogether 785 proteins were quantified from each tear sample using SWATH strategy and as these protein expression levels were compared between baseline and 12-month follow-up, three distinct patient groups were identified. We evaluated how these patient groups differed in their protein expression levels at baseline and discovered that the patients with increased levels of pro-inflammatory proteins and decreased levels of protective proteins benefitted most from the medication switch.

Multicenter, Randomized, Controlled Study Comparing Tafluprost/Timolol Fixed Combination with Latanoprost/Timolol Fixed Combination in Primary Open-Angle Glaucoma and Ocular Hypertension.

INTRODUCTION: This was the first exploratory randomized controlled study to compare the efficacy and safety of a preserved tafluprost/timolol fixed combination (TAF/TIM) with a preserved latanoprost/timolol fixed combination (LAT/TIM). METHODS: This prospective, randomized, open-label study was conducted in Japanese patients with primary open-angle glaucoma, including normal-tension glaucoma or ocular hypertension. Following a 4-week LAT/TIM run-in period, eligible patients entered a 12-week treatment period, during which they received either LAT/TIM or TAF/TIM. The efficacy endpoint was the change in intraocular pressure (IOP) from baseline to week 12 and the safety endpoints included the changes from baseline to week 12 in superficial punctate keratopathy (SPK) score, tear breakup time (TBUT), and hyperemia score, as well as adverse events (AEs). At week 6, ocular symptoms were evaluated using a questionnaire. RESULTS: In total, 131 patients provided informed consent. Of these, 115 completed the run-in period and were assigned to receive TAF/TIM (n = 60) or LAT/TIM (n = 55). At week 12, there were no significant differences between the TAF/TIM and LAT/TIM groups in the change from baseline in trough IOP and IOP at 4-6 h after instillation. There were no significant differences between the two groups in the change from baseline to week 12 in SPK score, TBUT, and hyperemia score. However, only in the TAF/TIM group, the total SPK score and the inferior cornea SPK score were significantly lower at week 12 compared with baseline. Eye irritation and eye pain were significantly decreased in the TAF/TIM group compared with the LAT/TIM group. Two treatment-related AEs were reported in the TAF/TIM group (3.3%) and none in the LAT/TIM group, while no serious AEs were reported in either group. CONCLUSION: TAF/TIM is as effective as LAT/TIM in terms of IOP-reducing effect, with fewer ocular symptoms. TAF/TIM was associated with a significant improvement in SPK scores. TRIAL REGISTRATION: UMIN Clinical Trials Registry Identifier, UMIN000023862. FUNDING: Santen Pharmaceutical Co., Ltd., Osaka, Japan.

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.

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.

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.

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.