Is Exposure to Intrapartum Prostaglandins for Labor Induction Associated with a Lower Incidence of Neonatal Respiratory Distress Syndrome?

OBJECTIVE: Respiratory distress syndrome (RDS) is implicated in 30% of neonatal deaths. Since prostaglandins promote surfactant secretion and labor is associated with a lower risk of RDS in term neonates, it is plausible that synthetic prostaglandin (sPG) exposure is associated with a lower risk of RDS. Thus, we evaluated the association between sPG exposure and RDS in neonates born after the induction of labor (IOL). STUDY DESIGN: Secondary analysis of women with singleton pregnancies undergoing IOL at 340/7 to 420/7 weeks in the nuMoM2b study, a multicenter prospective cohort of nulliparous women. RDS rates and secondary neonatal outcomes in neonates with intrapartum sPG exposure were compared with those who had IOL with non-sPG methods (e.g., balloon catheter, amniotomy, oxytocin, and laminaria). Logistic regression models estimated the association of sPG with RDS and with secondary outcomes after adjustment for clinical and demographic factors (including gestational age). A sensitivity analysis was performed in which analysis was restricted to those with an admission cervical dilation ≤2 cm. RESULTS: Of 10,038 women in the total cohort, 3,071 met inclusion criteria; 1,444 were exposed and 1,627 were unexposed to sPGs. Antenatal corticosteroid exposure rates were low (3.0%) and similar between groups. In univariable analysis, neonates with sPG exposure had higher rates of RDS (3.2 vs. 2.0%, odds ratio [OR]: 1.59, 95% confidence interval [CI]: 1.01-2.50). This relationship was similar by gestational age at delivery (term vs. preterm, interaction p = 0.14). After adjustment, the association between sPG and RDS was no longer significant (adjusted odds ratio: 1.4, 95% CI: 0.9-2.3). When analysis was restricted to subjects with admission cervical dilation of ≤2 cm, there was also no association between sPG exposure and RDS. CONCLUSION: In pregnancies between 34 and 42 weeks of gestation, exposure to sPG for cervical ripening or labor induction was not associated with newborn RDS. KEY POINTS: · RDS is implicated in 30% of neonatal deaths.. · sPG exposure was not associated with RDS.. · Avoiding preterm birth remains crucial in RDS prevention..

Medical anti-glaucoma therapy: Beyond the drop.

Barriers to effective medical therapy are numerous and include difficulties with effective and sustained control of intraocular pressure (IOP) and adherence to prescribed anti-glaucoma drop regimens. In an effort to circumvent these challenges, a number of new anti-glaucoma therapies with sustained effects have emerged. Methods for sustained delivery of prostaglandin analogs are being intensely investigated and many are in human clinical trials. Intracameral devices include the following: Allergan's Durysta™ Bimatoprost SR, Envisia Therapeutics' ENV515 travoprost implant, Glaukos' iDose™ , Ocular Therapeutix's OTX-TIC travoprost implant, and Santen's polycaprolactone implant with PGE2-derivative DE-117. Other prostaglandin-based technologies include Allergan's bimatoprost ring (placed in the conjunctival fornix), Ocular Therapeutics' OTX-TP intracanalicular travoprost implant, subconjunctival latanoprost in a liposomal formulation, and the PGE2 derivative PGN 9856-isopropyl ester that is applied to the periorbital skin. Exciting breakthroughs in gene therapy include using viral vectors to correct defective genes such as MYOC or to modulate gonioimplant fibrosis, CRISPR technology to edit MYOC or to alter aquaporin to reduce aqueous humor production, and siRNA technology to silence specific genes. Stem cell technology can repopulate depleted tissues or, in the case of Neurotech's Renexus® NT-501 intravitreal implant, serve as a living drug delivery device that continuously secretes neurotrophic factors. Other unique approaches involve nanotechnology, nasal sprays that deliver drug directly to the optic nerve and noninvasive alternating current stimulation of surviving cells in the optic nerve. Over time these modalities are likely to challenge the preeminent role that drops currently play in the medical treatment of glaucoma in animals.

Do We Conform with European Glaucoma Society Guidelines in the Medical Treatment of Primary Open-Angle Glaucoma/Ocular Hypertension? Data from a Real-Life Practice.

Purpose: To evaluate the prescribing habits of glaucoma specialists and of general ophthalmologists, and reveal the conformance with European Glaucoma Society (EGS) guidelines in the medical treatment of primary open-angle glaucoma (POAG) and ocular hypertension (OHT). Methods: Patients receiving medical treatment for POAG/OHT in the glaucoma clinic comprised the "naive group." Patients having a diagnosis and a treatment for POAG/OHT initiated in another center before presentation comprised the second group and were named as "treatment initiated elsewhere" (TIEW). All patients were retrospectively evaluated from the patients' charts. The outcome measures included the percentage of eyes treated with monotherapy, the molecule groups preferred, and the change in prescription trends over the years in both groups. Results: Seventy-two subjects were included in the naive group and 135 subjects in TIEW group. The rate of monotherapy was 76% and 36% in both groups, respectively. The molecule number was significantly higher in the TIEW group compared with naive group (1.98 ± 0.89 vs. 1.28 ± 0.56, P < 0.001). Until 2003, beta blockers, and in the 2003-2008 period, prostaglandin analogs (PGAs) were the mostly prescribed drugs in glaucoma clinic. From 2009, the rate of PGAs declined, with PGAs being replaced by combination drugs and alfa-2 agonists. Conclusions: Overtreatment rate was high among patients receiving a diagnosis and a treatment by general ophthalmologists, whereas glaucoma specialists were found to conform with EGS guidelines. A shift toward polypharmacy was observed from 2000 to 2017. The common guidelines to evaluate and treat glaucoma need to be adopted by the general ophthalmologists in their real-life practice.

Effect of Prostaglandin Analogues on Central Corneal Thickness: 3-Year Follow-up Results.

PURPOSE: To evaluate the effects of each subgroup of prostaglandin analogues (PGAs) on central corneal thickness (CCT) in patients with normal tension glaucoma (NTG). METHODS: We retrospectively reviewed 55 eyes of 55 patients with NTG who were receiving PGA therapy. Patients who were treated with 0.005% latanoprost (16 eyes), 0.0015% tafluprost (16 eyes), or 0.004% travoprost (23 eyes) monotherapy were included. CCT assessments were performed at baseline and 1, 2, and 3 years after initiation of treatment. RESULTS: In the NTG group, the mean CCT showed a decreasing trend, and there was a significant difference in mean CCT at 1, 2, and 3 years compared with baseline (baseline, 538.16 ± 32.14; 1 year, 526.55 ± 37.30 µm [p = 0.00]; 2 years, 521.67 ± 36.79 µm [p = 0.00]; 3 years, 520.43 ± 36.88 µm [p = 0.00]). The reduction of CCT was confirmed by subgroup analysis. In the 0.005% latanoprost group, mean CCT was decreased at 1 year (p = 0.11), 2 years (p = 0.00), and 3 years (p = 0.02). In the 0.0015% tafluprost group and the 0.004% travoprost group, mean CCT was also significantly decreased at all years (p = 0.00). No statistical difference was observed between the NTG subgroups (p = 0.06). CONCLUSIONS: Topical therapy with PGAs appeared to cause a significant decrease in CCT reduction in patients with NTG. A long-term follow-up study including more participants is needed.

Orbital Fat Volume After Treatment with Topical Prostaglandin Agonists.

Purpose: Topical prostaglandin analogs (PGAs) are common treatment for primary open-angle glaucoma (POAG) but reportedly may cause adnexal fat atrophy. We asked if patients with POAG treated with PGAs have abnormalities in orbital fat volume (OFV). Methods: We studied 23 subjects with POAG who had never experienced intraocular pressure (IOP) exceeding 21 mm Hg and were treated long term with PGAs, in comparison with 21 age-matched controls. Orbital volume, non-fat orbital tissue volume, and OFV were measured using high-resolution magnetic resonance imaging. Results: Subjects with POAG had been treated with PGAs for 39 ± 19 months (SD) and were all treated within the 4 months preceding study. In the region from trochlea to orbital apex, OFV in POAG was significantly less at 9.8 ± 1.9 mL than in the control subjects at 11.1 ± 1.3 mL (P = 0.019). However, between the globe-optic nerve junction (GONJ) and trochlea, OFV was similar in both groups. Width and cross sectional area of the bony orbit were significantly smaller in POAG than in controls (P < 0.0001). Posterior to the GONJ, the average orbital cross-sectional area was 68.2 mm2 smaller, and the orbital width averaged 1.5 mm smaller throughout the orbit, in patients with POAG than in controls. Conclusions: Patients with POAG who have been treated with PGAs have lower overall OFV than controls, but OFV in the anterior orbit is similar in both groups. Lower overall OFV in POAG may be a primary association of this disorder with a horizontally narrower bony orbit, which may be a risk factor for POAG at nonelevated IOPs.

Matrix Metalloproteinases and Glaucoma Treatment.

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade extracellular matrix (ECM) components such as collagen and have important roles in multiple biological processes, including development and tissue remodeling, both in health and disease. The activity of MMPs is influenced by the expression of MMPs and tissue inhibitors of metalloproteinase (TIMPs). In the eye, MMP-mediated ECM turnover in the juxtacanalicular region of the trabecular meshwork (TM) reduces outflow resistance in the conventional outflow pathway and helps maintain intraocular pressure (IOP) homeostasis. An imbalance in the MMP/TIMP ratio may be involved in the elevated IOP often associated with glaucoma. The prostaglandin analog/prostamide (PGA) class of topical ocular hypotensive medications used in glaucoma treatment reduces IOP by increasing outflow through both conventional and unconventional (uveoscleral) outflow pathways. Evidence from in vivo and in vitro studies using animal models and anterior segment explant and cell cultures indicates that the mechanism of IOP lowering by PGAs involves increased MMP expression in the TM and ciliary body, leading to tissue remodeling that enhances conventional and unconventional outflow. PGA effects on MMP expression are dependent on the identity and concentration of the PGA. An intracameral sustained-release PGA implant (Bimatoprost SR) in development for glaucoma treatment can reduce IOP for many months after expected intraocular drug bioavailability. We hypothesize that the higher concentrations of bimatoprost achieved in ocular outflow tissues with the implant produce greater MMP upregulation and more extensive, sustained MMP-mediated target tissue remodeling, providing an extended duration of effect.

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.

Cystoid macular edema related to cataract surgery and topical prostaglandin analogs: Mechanism, diagnosis, and management.

Cystoid macular edema (CME) is a form of macular retina thickening that is characterized by the appearance of cystic fluid-filled intraretinal spaces. It has classically been diagnosed upon investigation after a decrease in visual acuity; however, improvements in imaging technology make it possible to noninvasively detect CME even before a clinically significant decrease in central vision. Risk factors for the development of CME include diabetic retinopathy, retinal vein occlusion, uveitis, and cataract surgery. It has been proposed that eyes with elevated intraocular pressure after cataract surgery, including those treated with prostaglandin analog eye drops, may be at higher risk for the development of CME. We summarize the current knowledge of the molecular mechanisms underlying CME, the potential role of ocular surgery and topical glaucoma medication in increasing the risk of CME, the newly developed imaging methods for diagnosing CME, and the clinical management of CME.

Prostaglandin analogue drops for the treatment of soft tissue expansion and exophthalmos in patients with inactive thyroid eye disease.

OBJECTIVE: Thyroid eye disease (TED) is characterized by an inflammatory response leading to soft tissue expansion within the bony orbit, which may cause exophthalmos. Studies of glaucoma patients reported periorbital fat atrophy after treatment with prostaglandin analogue drops. We hypothesize that owing to this side effect, prostaglandin analogue drops may benefit patients with TED-induced exophthalmos. DESIGN: Interventional prospective pilot study. PARTICIPANTS: Five adults with inactive TED and exophthalmos treated with a single daily drop of bimatoprost to both eyes for 6 months. METHODS: The effect of treatment was evaluated by clinical examinations, Hertel exophthalmometry, marginal reflex distance (MRD), and comparison of digital photographs from before and after treatment by 3 masked oculoplastic surgeons. Patients' subjective satisfaction was recorded as well. RESULTS: Hertel exophthalmometry showed an improvement in exophthalmos after treatment in 3 patients and no change in 2. Both MRD1 and MRD2 increased (for MRD2 p = 0.007). Two observers correctly identified the photograph taken after treatment in 4 patients, and the third observer correctly identified 2 patients and was indecisive about the others. Four patients reported an improvement in their appearance, although additional eyelid retraction was observed. Adverse effects were minimal. CONCLUSION: Topical prostaglandin analogue treatment of TED-associated exophthalmos appears safe. Although this pilot study was statistically underpowered to show positive results, our findings suggest a treatment-related reduction in periorbital fat volume in most cases and a subjective improvement in appearance. These findings have potential implications for the treatment of exophthalmos in the clinical setting, but more research is required.

Shortening of Interpupillary Distance after Instillation of Topical Prostaglandin Analog Eye Drops.

PURPOSE: To investigate changes in the interpupillary distance (IPD) after continual instillation of topical prostaglandin analogs (PGAs) in glaucoma patients as an objective indicator of prostaglandin-associated periorbitopathy (PAP). DESIGN: Retrospective, comparative case series. METHODS: A total of 152 institutional patients with glaucoma were enrolled in this study. Inclusion criteria were visual acuities exceeding 10/20 bilaterally and no intraocular surgery during observation. Intervention/observation procedures: First-time bilateral instillation of bimatoprost, travoprost, latanoprost, or tafluprost and IPDs measured by automatic refractometry. IPDs, intraocular pressures (IOPs), and refractive errors were measured before and after continual drug administration (treatment, 2-24 months). MAIN OUTCOME MEASUREMENTS: Post-treatment changes in IPDs. A total of 61 untreated patients served as controls. RESULTS: The IPDs shortened significantly (P < 0.001) after treatment (-0.80 ± 2.1 mm); the IPDs of control subjects remained unchanged (0.05 ± 0.96 mm; P = 0.69). The IPD change after bimatoprost instillation (-2.20 ± 0.97 mm) was significantly (P < 0.001) greater than with other PGAs (-0.65 ± 2.09 mm). The IOPs decreased significantly (P < 0.001) (-3.7 ± 4.3 mm Hg); the refractive errors did not change significantly (P < 0.099) (-0.07 ± 0.69 diopter) post-treatment. The percentages of subjects with 2-mm or greater decreases in IPD after bimatoprost, travoprost, latanoprost, or tafluprost were 85.7%, 20.0%, 18.2%, and 17.2%, respectively, and with 3-mm or greater decreases in IPD 35.7%, 12.0%, 14.5%, and 12.1%, respectively. The specificities were 93.4% and 100% in the control group, respectively, with IPD threshold changes of 2 and 3 mm or more, respectively. CONCLUSIONS: The IPD decreased significantly after topical PGAs within 24 months. The effect was significantly greater with bimatoprost than with other PGAs. The noninvasive, immediate automatic refractometry measurement may be an objective numerical indicator of PAP.

Glaucoma: Current treatment and impact of advanced drug delivery systems.

The human eye being a complex and a very sensitive organ makes the drug delivery task challenging. An increase in the intra-ocular pressure at the aqueous humour leads to glaucoma which is not only indecipherable but can also be the reason of blindness for many. The presently available marketed formulations using anti-glaucoma drugs have issues of either difficulty in crossing the blood- retinal barrier or lower systemic bioavailability. Hence, the drugs having lower therapeutic index would need to be administered frequently, which eventually lead to deposition of concentrated solutions at ocular site, producing toxic effects and cellular damage to the eye. To overcome these drawbacks the novel drug delivery systems like In-situ gels, liposomes, niosomes, hydrogel, dendrimers, nanoparticles, solid lipid nanoparticles, Microneedles or ocular inserts play an important role to enhance the therapeutic efficacy of the anti-glaucomic drugs. The present review briefs the current treatments in terms of drugs used and in detail the impact of utilizing the above mentioned novel drug delivery systems in the treatment of glaucoma.

Effect of vitamin-E integration on delivery of prostaglandin analogs from therapeutic lenses.

HYPOTHESIS: Glaucoma is effectively treated by prostaglandin analogs. Low corneal bioavailability (<5%) of daily-instilled prostaglandin drops complemented by frequent application results in low patient compliance (<50%). One alternative route is ocular delivery via commercial hydrogel contact lens. Commercial lenses, however, release prostaglandins rapidly in a few hours owing to their small molecular size, resulting in toxic side-effects. Here, the feasibility of sustained prostaglandin, namely bimatoprost and latanoprost delivery by vitamin-E integrated polymeric hydrogels is explored. Inclusion of these barriers is expected to augment transport resistance and influence delivery rates. EXPERIMENTS: Lens immersion in vitamin-E concentrated ethanol is done to enable formation of nano-barrier depots. FINDINGS: Pilot in vitro studies indicate that ACUVUE® OASYS® and ACUVUE® TruEye™ lenses loaded with ∼0.2 g of vitamin-E/g of hydrogel effectively prolong bimatoprost dynamics by 10-40-fold, delivering therapeutic dosages for >10 days. Incorporation of vitamin-E into the lenses retains visible light transmission and other properties. Further, vitamin-E integration does not influence latanoprost transport. An in vivo model involving coupled mass transport in the lens and post-lens tear film (POLTF) domains predicts >50% corneal bioavailability of bimatoprost delivered via modified lenses.

Prostaglandin analogues and nitric oxide contribution in the treatment of ocular hypertension and glaucoma.

In patients with ocular hypertension or glaucoma, all treatments aim to lower intraocular pressure (IOP) by modulating aqueous humour (AH) production and/or uveoscleral and trabecular meshwork/Schlemm's canal AH drainage. PG analogues are considered to be the 'gold standard' treatment and are the most frequently used IOP-lowering agents. Recent data support an important role for NO in regulating IOP. Thus, novel PG analogues carrying a NO-donating moiety were recently advanced. Latanoprostene bunod (LBN) and NCX 470, NO-donating derivatives of latanoprost and bimatoprost, respectively, are examples of such compounds. LBN ophthalmic solution, 0.024% (Vyzulta™), showed greater IOP-lowering efficacy compared with that of Xalatan® (latanoprost ophthalmic solution, 0.005%) or 0.5% timolol maleate in clinical settings. NCX 470 was found to be more effective than bimatoprost in animal models of ocular hypertension and glaucoma. Selective EP2 receptor agonists (i.e. taprenepag isopropyl, omidenepag isopropyl and aganepag isopropyl) and non-selective prostanoid receptor agonists (i.e. ONO-9054, sepetaprost isopropyl) that concomitantly stimulate FP and EP3 receptors have also been shown to hold promise as effective IOP-lowering agents. 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.

Comparative Effectiveness of Generic Latanoprost Versus Branded Prostaglandin Analogs for Primary Open Angle Glaucoma.

PURPOSE: The purpose of the study is to determine the comparative effectiveness of generic latanoprost (GL) to its branded (BL) counterpart and other brand-name prostaglandin analogs (bPGAs) in preventing the need for additional therapy in the treatment of primary open angle glaucoma (POAG). METHODS: Retrospective cohort study using US commercial medical claims data. All new POAG patients from 2000 to 2015 who initiated treatment with either GL or BL were included. Exclusion occurred for having less than 2 years of time in the plan prior to diagnosis, previous use of glaucoma medications, or any diagnosis of glaucoma other than POAG at any time. Analyses compared GL to BL and also to those who received any branded PGA after 2011 (when the generic became available). Cox proportional hazard regression was used to assess the hazards of filling a prescription for a second IOP-lowering medication or having surgical intervention, individually and either outcome combined. RESULTS: A total of 6317 and 4150 POAG patients were treated with GL and BL, respectively. After 2010, 6317 GL and 3703 brand-name prostaglandin analog (bPGA) POAG patients met criteria for inclusion. After adjustment, compared to BL, the GL conferred a reduced hazard of having a glaucoma procedure performed (hazard ratio [HR] = 0.72, 95% CI: 0.62-0.84, p < 0.001) and the combined outcome (HR = 0.90, 95% CI: 0.83-0.97, p = 0.006) but was not associated with having a second IOP medication (HR = 0.95, 95% CI: 0.87-1.03, p = 0.18). Compared to the bPGAs, however, GL conferred a reduced hazard in each comparison (second IOP medication HR = 0.87, 95% CI: 0.81-0.94, p < 0.001; surgery HR = 0.70, 95% CI: 0.61-0.81, p < 0.001; combined HR = 0.85, 95% CI: 0.79-0.92, p < 0.001). Sensitivity analyses confirmed these findings. CONCLUSIONS: GL was no less and possibly more effective in preventing the need for additional intervention than branded PGAs.

Micropulse laser trabeculoplasty on pseuodexfoliation glaucoma patients under topical prostaglandin analogue monotherapy: 1-year results.

PURPOSE: To evaluate the effectiveness of a single session of micropulse laser trabeculoplasty (MLT) to lower intraocular pressure (IOP) in patients with pseudoexfoliation glaucoma (PEXG). METHODS: In this single-center, one-arm, prospective study patients with PEXG under prostaglandine analogue monotherapy with inadequate IOP control were treated with 360° 532-nm MLT. Patients were evaluated at 1 day, 1 month, 3 months, 6 months, and 12 months post-MLT while they were treated with the same drug regimen as pre-MLT. Mean IOP reduction and percentage of IOP change during the follow-up were calculated. Cases that required any further intervention, like additional hypotensive medication, laser or surgical therapy, throughout the study period were considered failures and removed from the study. RESULTS: Twenty-seven eyes (27 patients, 17 male) were included in the study. The age of the patients was 72.37 ± 6.29 years and the baseline IOP was 20.41 ± 1.87 mmHg. Treatment with MLT resulted in significantly lower IOP at 1, 3, 6, and 12 months after MLT compared to baseline (p < 0.0001 for all comparisons). By the end of the study, 52.17% of the PEXG eyes demonstrated a ≥ 20% IOP reduction compared to baseline. Four eyes (14.81%) did not respond to MLT (three eyes at 3 months and one eye at 6 months after trabeculoplasty) and were considered failures since they required additional intervention. CONCLUSIONS: Micropulse laser trabeculoplasty appears to be an effective method to lower IOP in patients with PEXG up to 12 month of follow-up period. TRIAL REGISTRATION: The study is registered on www.ClinicalTrials.gov with registration number NCT03483402.

The Effect of Prostaglandin Analogue Bimatoprost on Thyroid-Associated Orbitopathy.

Purpose: We characterize the effect of bimatoprost on orbital adipose tissue in thyroid-associated orbitopathy (TAO) with clinicopathologic correlation. Methods: Orbital adipose-derived stem cells (OASCs) from types 1 and 2 TAO and control patients with and without exposure to 1 µm bimatoprost were examined via immunohistochemistry, RT-PCR, and Western blot for cell viability, migration capacity, lipid content, adipocyte morphology, mitochondrial content, and levels of adipogenic markers. A retrospective chart review was performed for clinicopathologic correlation. In mice, optical coherence tomography and pattern electroretinography were performed at baseline and at 1 month following a retrobulbar injection of bimatoprost, followed by orbital exenteration for histopathologic examination. Results: Types 1 and 2 TAO-derived cells had a significantly higher migration capacity and lipid content than those of healthy controls. With the addition of bimatoprost, types 1 and 2 TAO and control adipocytes exhibited a significant decrease in lipid content with morphologic transformation into smaller and multilocular lipid droplets, and an increase in mitochondrial load and UCP-1 expression consistent with an increase in brown adipose tissue turnover. Retrobulbar injection of bimatoprost in mice did not alter the gross morphology, retinal thickness, or ganglion cell function in vivo. Conclusions: Bimatoprost inhibits adipogenesis in OASCs and upregulates pathways involved in the browning of adipocytes. Furthermore, retrobulbar injection of bimatoprost is tolerated without immediate adverse effects in mice. Our results suggest a potential future application of prostaglandin analogues in the treatment of TAO.

The Effect of Prostaglandin Analogues on the Ciliary Zonular Fibers of the Rabbit Crystalline Lens.

PURPOSE: To evaluate the influence of prostaglandin (PG) analogues on the ciliary zonular fibers of the crystalline lens using scanning electron microscopy (SEM) of rabbit eyes, and to measure the matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) levels of the aqueous humor and crystalline lens treated with topical PG analogues Methods: Fifty eyes from 25 New Zealand white rabbits were divided into five groups of five rabbits each. In the control group, balanced salt solution was administered via the topical route once a day to the eyes. The benzalkonium chloride (BAC) group was treated with 0.02% BAC, the Latanoprost group with 0.005% latanoprost, the Travoprost group with 0.004% Travoprost, and the Bimatoprost group with 0.03% Bimatoprost for 10 months. We examined the ciliary zonular fibers using SEM. We also measured the MMP and TIMP levels of the aqueous humor and crystalline lens. RESULTS: SEM revealed some splitting of zonular fibers in eyes treated with topical PG analogues when compared with the control and BAC groups. The MMP-1 and TIMP-1 levels after treatment with the PG analogues did not differ significantly from the control and BAC groups (P > 0.05). There was no significant difference in MMP-1, MMP-3, TIMP-1, and MMP-1/TIMP-1 levels in the lens among all five groups. CONCLUSIONS: PG analogues may induce zonular change in rabbits microscopically. There was no association between zonular changes and the levels of certain types of MMP or TIMP in the aqueous humor or crystalline lens after topical treatment with PG analogues.

Role of the water-drinking test in medically treated primary open angle glaucoma patients.

PURPOSE: The water-drinking test (WDT) has recently re-emerged as a possible way to determine the competency of the trabecular meshwork. We performed a prospective interventional study to test the hypothesis that the WDT could be useful in assessing fluctuations in patients undergoing treatment for primary open angle glaucoma (POAG). METHODS: We included 122 patients; 62 on medical treatment for POAG (n=123 eyes) and 60 controls (n=120 eyes). The study group had been on intraocular pressures (IOP) lowering treatment continuously for at least 3months with stable IOP. The WDT was performed during fasting and was considered positive if it fluctuated ≥6mmHg. RESULTS: The patients on medical treatment had a mean age of 50.56±18.45 years vs. 51.35±11.22 for the controls (P=0.34); with 71% being female in the study group and 77% in the control group. In the study group; 52% were on beta blockers (n=64), 27% combination of two or more medications (n=33), 19% prostaglandin analogues (n=24) and 2% alpha agonists (n=2). The WDT was positive in 17.07% (n=21) in the study group and 2.5% (n=3) in the control group (P=0.0001). The mean fluctuation was 7.14±2.15mmHg in the study group and 6.00±0mmHg in the controls (P=0.33). A positive WDT was found in 33.33% (n=11) of those on combination therapy; 12.5% (n=3) prostaglandin analogues and 10.94% (n=7) beta blockers (P=0.03). Combination therapy had the highest positive WDT fluctuation (7.54±2.87) followed by prostaglandin analogues (7.00±1.00) and beta blockers (6.57±0.78) with a P value of 0.44. CONCLUSIONS: The WDT can identify significant fluctuations in eyes with POAG that are medically treated.

Effect of a punctal plug on ocular surface disease in patients using topical prostaglandin analogues: a randomized controlled trial.

IMPORTANCE: Ocular surface disease (OSD) is common and can reduce treatment compliance and quality of life. BACKGROUND: To determine whether a punctal plug improves OSD and reduces intraocular pressure (IOP) in patients using prostaglandin analogue monotherapy. DESIGN: Randomized controlled trial. PARTICIPANTS: Sixty eligible subjects aged >18 years with symptomatic OSD from glaucoma clinics were invited to participate. Lacrimal or glaucoma surgery, lid malposition and contact lens wear were exclusion criteria. METHODS: One eye received an inferior punctal plug, leaving the fellow eye as a control. MAIN OUTCOME MEASURES: Ocular surface disease index (OSDI), tear film breakup time (TF-BUT), Oxford cornea score, tear osmolarity and IOP were compared at baseline and 6 weeks by masked investigators. RESULTS: From 60 eligible, 48 (80.0%) participated (mean age 69.6 years; 60.0% female). OSDI reduced following plug insertion (mean difference [MD] 14.5, 95% confidence interval [CI] 5.06-23.94, P < 0.001). Compared to control eyes, in eyes receiving plugs the TF-BUT increased (MD 2.3 s, 95% CI 1.4-3.2, P < 0.001), the Oxford cornea score decreased (MD 0.5, 95% CI 0.3-0.7, P < 0.001), and tear osmolarity decreased (MD 10 mOsm/L, 95% CI 3.5-16.5, P = 0.003). Punctal plugs resulted in a significantly lowered IOP (MD 1.5 mmHg, 95% CI 0.1-2.9, P = 0.032). Sub-group analyses showed similar efficacy regardless of prostaglandin preservative status or lubricant drop use. Plugs were well tolerated but extrusion occurred in 8.5%, and epiphora increased in 6.5% eyes. CONCLUSIONS AND RELEVANCE: Punctal plug insertion improves subjective and objective measures of OSD and results in a reduced IOP in patients with symptomatic ocular surface disease using prostaglandin analogue monotherapy.