Travoprost Intracameral Implant Demonstrates Superior IOP Lowering Versus Topical Prostaglandin Analog Monotherapy in Patients with Open-Angle Glaucoma or Ocular Hypertension.

INTRODUCTION: This study was conducted to analyze and compare the intraocular pressure (IOP) treatment effect of the slow-eluting (SE) travoprost intracameral implant to the IOP treatment effect of topical prostaglandin analog (PGA) monotherapy in a subgroup of subjects who were on pre-study PGA monotherapy prior to enrollment in the two pivotal phase 3 trials of the travoprost intracameral implant. METHODS: A combined study population of 133 subjects from two phase 3 trials, who were on topical PGA monotherapy at screening, subsequently underwent a washout period from their topical PGA, and then were randomized and administered an SE travoprost intracameral implant. The subjects were analyzed for the IOP treatment effects of the pre-study topical PGA monotherapy and the in-study SE travoprost intracameral implant. Paired t-tests were used to compare the difference in screening minus post-washout baseline IOP versus month 3 minus post-washout baseline IOP. The IOP-lowering efficacy in eyes administered an SE travoprost intracameral implant was compared to the IOP lowering in the same eyes while on a topical PGA monotherapy prior to study entry. RESULTS: Pre-study topical PGA monotherapy and the SE travoprost intracameral implant demonstrated IOP treatment effects of -5.76 mmHg and -7.07 mmHg, respectively. The IOP-lowering treatment effect was significantly greater by 1.31 mmHg for the SE travoprost intracameral implant relative to pre-study PGA monotherapy (95% confidence interval: -2.01, -0.60; P = 0.0003). CONCLUSIONS: The SE travoprost intracameral implant demonstrated superior IOP-lowering treatment effect versus pre-study topical PGA monotherapy with a superiority margin that was both statistically significant and clinically meaningful. The greater IOP reduction from baseline while on the SE implant versus pre-study topical PGA monotherapy may be a reflection of the optimized adherence and continuous elution of PGA therapy into the anterior chamber achieved with the SE travoprost intracameral implant. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT03519386 and NCT03868124.

Sustained Release Therapies with the Prostaglandin Analogues Intracameral Implants.

The travoprost intracameral implant was recently approved by the US Food and Drug Administration for sustained release medical treatment of open-angle glaucoma in the USA. The approval represents a substantial and progressive step forward in the area of sustained-release glaucoma therapy. Topical intraocular pressure-lowering medications for the treatment of glaucoma are faced with a host of challenges for long-term and usually lifelong care. A changing paradigm in glaucoma management involves first-line interventions with laser modalities, micro-invasive surgeries, and sustained-release treatment platforms. Future needs in the area of sustained-release therapy include a non-prostaglandin drug delivery platform and longer-term treatments that do not require surgical reintervention.

Travoprost Intracameral Implant for Open-Angle Glaucoma or Ocular Hypertension: 12-Month Results of a Randomized, Double-Masked Trial.

INTRODUCTION: This prospective, multicenter, randomized, double-masked pivotal phase 3 trial evaluated the efficacy and safety of the travoprost intracameral SE-implant (slow-eluting implant, the intended commercial product) and FE-implant (fast-eluting implant, included primarily for masking purposes) compared to twice-daily (BID) timolol ophthalmic solution, 0.5% in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). METHODS: The trial enrolled adult patients with OAG or OHT with an unmedicated mean diurnal intraocular pressure (IOP) of ≥ 21 and unmedicated IOP ≤ 36 mmHg at each diurnal timepoint (8 A.M., 10 A.M., and 4 P.M.) at baseline. The eligible eye of each patient was administered an SE-implant, an FE-implant or had a sham administration procedure. Patients who received an implant were provided placebo eye drops to be administered BID and patients who had the sham procedure were provided timolol eye drops to be administered BID. The primary efficacy endpoint, for which the study was powered, was mean change from baseline IOP at 8 A.M. and 10 A.M. at day 10, week 6, and month 3. Non-inferiority was achieved if the upper 95% confidence interval (CI) on the difference in IOP change from baseline (implant minus timolol) was < 1.5 mmHg at all six timepoints and < 1 mmHg at three or more timepoints. The key secondary endpoint was mean change from baseline IOP at 8 A.M. and 10 A.M. at month 12. Non-inferiority at month 12 was achieved if the upper 95% CI was < 1.5 mmHg at both timepoints. Safety outcomes included treatment-emergent adverse events (TEAEs) and ophthalmic assessments. RESULTS: A total of 590 patients were enrolled at 45 sites and randomized to one of three treatment groups: 197 SE-implant (the intended commercial product), 200 FE-implant, and 193 timolol. The SE-implant was non-inferior to timolol eye drops in IOP lowering over the first 3 months, and was also non-inferior to timolol at months 6, 9, and 12. The FE-implant was non-inferior to timolol over the first 3 months, and also at months 6 and 9. Of those patients who were on glaucoma medication at screening, a significantly greater proportion of patients in the SE- and FE-implant groups (83.5% and 78.7%, respectively) compared to the timolol group (23.9%) were on fewer topical glaucoma medications at month 12 compared to screening (P < 0.0001, chi-square test). TEAEs, mostly mild, were reported in the study eyes of 39.5% of patients in the SE-implant group, 34.0% of patients in the FE-implant group and 20.1% of patients in the timolol group. CONCLUSIONS: The SE-travoprost intracameral implant demonstrated non-inferiority to timolol over 12 months whereas the FE-implant demonstrated non-inferiority over 9 months. Both implant models were safe and effective in IOP lowering in patients with OAG or OHT. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03519386.

Phase 3 Randomized Clinical Trial of the Safety and Efficacy of Travoprost Intraocular Implant in Patients with Open-Angle Glaucoma or Ocular Hypertension.

PURPOSE: To evaluate the safety and intraocular pressure (IOP)-lowering efficacy of 2 models of the travoprost intraocular implant (fast-eluting [FE] and slow-eluting [SE] types) from 1 of 2 phase 3 trials (the GC-010 trial). DESIGN: Multicenter, randomized, double-masked, sham-controlled, noninferiority trial. PARTICIPANTS: Patients with open-angle glaucoma or ocular hypertension having an unmedicated baseline mean diurnal IOP (average of 8 am, 10 am, and 4 pm time points) of ≥ 21 mmHg, and IOP of ≤ 36 mmHg at each of the 8 am, 10 am, and 4 pm timepoints at baseline. METHODS: Study eyes were randomized to the travoprost intraocular implant (FE implant [n = 200] or SE implant [n = 197] model) or to timolol ophthalmic solution 0.5% twice daily (n = 193). MAIN OUTCOME MEASURES: The primary outcome was mean change from baseline IOP in the study eye at 8 am and 10 am, at each of day 10, week 6, and month 3. Safety outcomes included adverse events (AEs) and ophthalmic assessments. RESULTS: Mean IOP reduction from baseline over the 6 time points ranged from 6.6 to 8.4 mmHg for the FE implant group, from 6.6 to 8.5 mmHg for the SE implant group, and from 6.5 to 7.7 mmHg for the timolol group. The primary efficacy end point was met; the upper limit of the 95% confidence interval of the difference between the implant groups and the timolol group was < 1 mmHg at all 6 time points. Study eye AEs, most of mild or moderate severity, were reported in 21.5%, 27.2%, and 10.8% of patients in the FE implant, SE implant, and timolol groups, respectively. The most common AEs included iritis (FE implant, 0.5%; SE implant, 5.1%), ocular hyperemia (FE implant, 3.0%; SE implant, 2.6%), reduced visual acuity (FE implant, 1.0%; SE implant, 4.1%; timolol, 0.5%), and IOP increased (FE implant, 3.5%; SE implant, 2.6%; timolol, 2.1%). One serious study eye AE occurred (endophthalmitis). CONCLUSIONS: The travoprost intraocular implant demonstrated robust IOP reduction over the 3-month primary efficacy evaluation period after a single administration. The IOP-lowering efficacy in both implant groups was statistically and clinically noninferior to that in the timolol group, with a favorable safety profile. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Prostaglandin analogs in ophthalmology.

Glaucoma is a major cause of irreversible blindness worldwide. Reducing intraocular pressure (IOP) is currently the only approach to prevent further optic nerve head damage. Pharmacotherapy is the mainstay of treatment for glaucoma patients. In recent years, a significant milestone in glaucoma treatment has been a transition to prostaglandin analogs (PGAs) as the first line of drugs. The rapid shift from traditional ß-blockers to PGAs is primarily due to their excellent efficacy, convenient once-a-day usage, better diurnal control of IOP, and systemic safety profiles. This review article aims to provide information regarding the various PGAs in practice and also the newer promising drugs.

Travoprost Liquid Nanocrystals: An Innovative Armamentarium for Effective Glaucoma Therapy.

To date, the ophthalmic application of liquid crystalline nanostructures (LCNs) has not been thoroughly reconnoitered, yet they have been extensively used. LCNs are primarily made up of glyceryl monooleate (GMO) or phytantriol as a lipid, a stabilizing agent, and a penetration enhancer (PE). For optimization, the D-optimal design was exploited. A characterization using TEM and XRPD was conducted. Optimized LCNs were loaded with the anti-glaucoma drug Travoprost (TRAVO). Ex vivo permeation across the cornea, in vivo pharmacokinetics, and pharmacodynamic studies were performed along with ocular tolerability examinations. Optimized LCNs are constituted of GMO, Tween® 80 as a stabilizer, and either oleic acid or Captex® 8000 as PE at 25 mg each. TRAVO-LNCs, F-1-L and F-3-L, showed particle sizes of 216.20 ± 6.12 and 129.40 ± 11.73 nm, with EE% of 85.30 ± 4.29 and 82.54 ± 7.65%, respectively, revealing the highest drug permeation parameters. The bioavailability of both attained 106.1% and 322.82%, respectively, relative to the market product TRAVATAN®. They exhibited respective intraocular pressure reductions lasting for 48 and 72 h, compared to 36 h for TRAVATAN®. All LCNs exhibited no evidence of ocular injury in comparison to the control eye. The findings revealed the competence of TRAVO-tailored LCNs in glaucoma treatment and suggested the potential application of a novel platform in ocular delivery.

Analysing the change in contrast sensitivity post-travoprost treatment in primary open-angle glaucoma patients using Spaeth Richman contrast sensitivity test.

OBJECTIVE: To determine the ability of the Internet-based Spaeth/Richman Contrast Sensitivity (SPARCS) in assessing the change in contrast sensitivity (both central and peripheral) post-treatment with travoprost 0.004%. DESIGN: This is a prospective observational study. METHODS AND PARTICIPANTS: Data of 62 eyes (33 patients) undergoing treatment for naïve POAG patients were analysed. Patients were followed up for a period of six months after starting topical travoprost (Travatan 0.004%, Alcon), and the change in central and peripheral CS was studied. RESULTS: Mean total SPARCS score at baseline was 69 ± 10.99, improved to 74.62 ± 9.50 after 6 months of therapy (p: 0.001) in all the glaucoma severity groups. Mean SPARCS score at baseline in mild glaucoma group was 72.05 ± 9.87, in the moderate glaucoma group, it was 62.23 ± 9.2, and in the severe glaucoma group, it was 59.36 ± 11.65. After 6 months of treatment with travoprost, the CS improved to 76.05 ± 8.36 in mild group, 76.69 ± 8.82 in moderate group and 67.18 ± 11.15 in severe group (p value: 0.014). The percentage change in the CS from baseline showed significant improvement in the superotemporal quadrant at 1 month (p value: 0.032), superonasal quadrant (p value: 0.049), inferotemporal quadrant at 3 months (p value: 0.003) and 6 months (p value: 0.039). Inferonasal quadrant was affected most by glaucoma. A statistically significant correlation was seen between total SPARCS score with MD and PSD. Correlation was also seen between the percentage change in CS and average RNFL thickness at 3 and 6 months. CONCLUSION: Both central and peripheral CS improve following IOP reduction with travoprost. Change in the CS has a significant correlation with RNFL thickness and the perimetric indices.

Identification of CB1 Ligands among Drugs, Phytochemicals and Natural-Like Compounds: Virtual Screening and In Vitro Verification.

Cannabinoid receptor type 1 (CB1) is an important modulator of many key physiological functions and thus a compelling molecular target. However, safe CB1 targeting is a non-trivial task. In recent years, there has been a surge of data indicating that drugs successfully used in the clinic for years (e.g. paracetamol) show CB1 activity. Moreover, there is a lot of promise in finding CB1 ligands in plants other than Cannabis sativa. In this study, we searched for possible CB1 activity among already existing drugs, their metabolites, phytochemicals, and natural-like molecules. We conducted two iterations of virtual screening, verifying the results with in vitro binding and functional assays. The in silico procedure consisted of a wide range of structure- and ligand-based methods, including docking, molecular dynamics, and quantitative structure-activity relationship (QSAR). As a result, we identified travoprost and ginkgetin as CB1 ligands, which provides a starting point for future research on the impact of their metabolites or preparations on the endocannabinoid system. Moreover, we found five natural-like compounds with submicromolar or low micromolar affinity to CB1, including one mixed partial agonist/antagonist viable for hit-to-lead phase. Finally, the computational procedure established in this work will be of use for future screening campaigns for novel CB1 ligands.

Generic benzalkonium chloride-preserved travoprost eye drops are not identical to the branded polyquarternium-1-preserved travoprost eye drop: Effect on cultured human conjunctival goblet cells and their physicochemical properties.

PURPOSE: To investigate the effect of polyquaternium-1 (PQ)-preserved and benzalkonium chloride (BAK)-preserved travoprost eye drops on viability of primary human conjunctival goblet cell (GC) cultures and on secretion of mucin and cytokines. Furthermore, to evaluate the physicochemical properties of the branded travoprost eye drop Travatan® and available generics. METHODS: The effect of travoprost eye drops was evaluated on GC cultures. Cell viability was assessed through lactate dehydrogenase (LDH) and tetrazolium dye (MTT) colorimetric assays. Mucin secretion was evaluated by immunohistochemical staining. Secretion of interleukin (IL)-6 and IL-8 was measured using BD Cytometric Bead Arrays. pH, viscosity, droplet mass, osmolality and surface tension were measured for all included eye drops. RESULTS: In the LDH assay, BAK travoprost caused significant GC loss after 2 hrs of incubation compared to the control. PQ travoprost caused no GC loss at any time point. Both PQ- and BAK travoprost caused secretion of mucin to the cytoplasma. No difference in IL-6 and IL-8 secretion was identified compared to controls. The pH values for the generics were lower (pH 6.0) than the pH value for Travatan (pH 6.7; p < 0.0001). The viscosity was lowest for Travatan, while the mean droplet mass was higher for Travatan (35 mg) than the generics (28-30 mg; p ≤ 0.0318). The osmolality and surface tension did not differ between the eye drops investigated. CONCLUSION: BAK travoprost caused GC loss, indicating that PQ preservation may be preferable in treatment of glaucoma. Furthermore, physicochemical properties of branded and generic travoprost eye drops can not be assumed to be identical.

Spanlastics nanovesicular ocular insert as a novel ocular delivery of travoprost: optimization using Box-Behnken design and in vivo evaluation.

Currently, travoprost is a synthetic prostaglandin F2α analogue used in the treatment of glaucoma, it is delivered by eye drop solution. Due to its very low bioavailability and patient non-compliance, the objective of the current study was to enhance its bioavailability, and prolong its release Spanlastic nano-vesicles gels were designed and optimized using Box-Behnken design. The optimized spanlastic nano-vesicles gel exhibited the lowest particle size (PS), polydispersity index (PDI) and the highest zeta potential (ZP), encapsulation efficiency (EE) and mucoadhesive strength was fabricated into spanlastic nano-vesicles ocular insert by solvent casting. In vivo studies showed enhanced bioavailability of travoprost spanlastic nano-vesicles gel and ocular insert compared to the marketed eye drops (travoswix®), as proven by their higher Cmax and AUC0-∞, in addition to being nonirritant to ocular surfaces. However, spanlastic nano-vesicles ocular insert showed more prolonged effect than spanlastic nano-vesicles gel. According to our study, it can be suggested that travoprost spanlastic nano-vesicles ocular insert is a novel ocular delivery system for glaucoma treatment.

A new look at the safety and tolerability of prostaglandin analogue eyedrops in glaucoma and ocular hypertension.

INTRODUCTION: In the last 25 years, topical prostaglandin analogues (PGAs) have emerged to become first line and first choice therapeutic options in the management of glaucoma and ocular hypertension (OHT). Although the short-term efficacy and safety of PGAs has been extensively investigated, less is known about their long term safety and tolerability. This gap in current knowledge is clinically relevant, because treatment-related adverse events and long-term tolerability issues are key determinants of the overall success of long-term therapy and the final outcome of a lifelong, symptomless disease like glaucoma. AREAS COVERED: We include selected evidence pertaining to the safety and tolerability of available and emerging PGA formulations. We also outline PGA formulations with different concentrations of the active ingredient, different preservatives, and preservative-free (PF) options. EXPERT OPINION: Undoubtedly PGAs will continue to play a major role in the medical therapy of glaucoma and OHT. Despite extensive literature and prolonged clinical experience with these agents worldwide, a number of areas that warrant further research have been identified in the present review. Recently launched novel PGAs, or those still in development offer new opportunities and future challenges.

Effect of Topical Prostaglandin Analogue Therapy on Central Corneal Thickness: A Systematic Review.

To investigate whether prostaglandin analogue (PGA) eyedrops have a significant effect on central corneal thickness (CCT), we conducted a systematic search of literature published from 2000 to 2021. Among the studies conducted on topical PGA therapy in open-angle glaucoma or ocular hypertension patients over 18 years old, prospective studies with CCT change as an outcome were included. A single-arm meta-analysis was conducted to assess the overall effect on CCT, and subgroup analysis according to exposure time of PGA eyedrops was also performed. We counted the number of articles that reported on severe events (CCT reduction of 25 µm or more) and obtained their proportion. The methodological quality was assessed by the McHarm tool. Twenty-two reports of prospective studies were selected. The results of the single-arm meta-analysis showed very high heterogeneity. Still, in subgroup analysis, when PGA was used for more than 6 months, heterogeneity was low, and a significant decrease in CCT was observed. Severe events were reported in two reports and occurred in 3.8% to 14.8% of participants. PGA eyedrop use may cause a clinically significant CCT decrease, requiring CCT follow-up.

Determination of five prostaglandin analogs in eyelash enhancing cosmetics by LC-MS/MS / 上海预防医学

Objective To determine bimatoprost， tafluprost ethyl amide， latanoprost， travoprost and tafluprost in eyelash enhancing cosmetics by establishing a LC-MS/MS method. Methods The samples were extracted with a 50% acetonitrile water solution. A salt mixture（4 g NaCl， 1 g MgSO4） was added to the solution to induce phase separation. After centrifugation and filtration， the analysis of five prostaglandin analogs was performed with an Agilent Poroshell 120 PFP-C18 （2.7 μm， 2.1 mm×100 mm） column， using 0.02% formic acid containing 5 mmol·L-1 Acetic acid amine and acetonitrile by gradient elution at a flow rate of 0.5 mL·min-1. The analytes were detected with electrospray ionization source in positive ion mode （ESI+） and multiple reaction monitoring （MRM）， and quantified by external standard curve. Results The results showed that it had a good linearity in the range of locatable ambit of concentration with correlation coefficients （r） larger than 0.999. The detection limit of five prostaglandin analogs （LOD） was 0.000 2‒1.5 μg·g-1. The spiked recoveries were 93.2% to 103.5% with a relative standard deviation （RSD） of 1.2% to 3.4%. Conclusion The method is simple， rapid and highly sensitive. It is suitable for the determination of five prostaglandin analogs in eyelash enhancing cosmetics.

Meta-analysis of efficacy between Travoprost and Timolol in treating primary open angle glaucoma / 国际眼科杂志(Guoji Yanke Zazhi)

@#AIM: To systematically evaluate the changes of hemodynamics, astigmatism and cytokines between travoprost and timolol in the treatment of primary open angle glaucoma(POAG)in Chinese adults.METHODS:Randomized controlled trials(RCTs)and cohort studies comparing the related efficacy of travoprost and timolol for POAG were retrieved from PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure(CNKI), Chinese Biomedical Literature Database(CBM), VIP database and Wanfang database. The search time was from January 1, 2015 to December 31, 2020. The literatures were screened according to the inclusion and exclusion criteria. After quality evaluation by Cochrane tools for RCTs and NOS scores for cohort studies, Review Manager 5.4 software was used for Meta-analyses to generate weighed-mean-difference(<i>WMD</i>)as effect size contrasting the efficacy of travoprost and timolol for the peak systolic velocity(PSV), the end diastolic velocity(EDV)and the resistance index(RI)of the central retinal artery(CRA)and the posterior ciliary artery(PCA), astigmatism, the plasma endothelin-1(ET-1), the serum matrix metalloproteinase(MMP), the tissue inhibitor of metalloproteinase-2(TIMP-2)of the aqueous humor and the serum TIMP-2. RESULTS:Totally 8 RCTs and 4 retrospective cohort studies were included with 1 192 patients.Meta-analysis showed that:compared with timolol group, the travoprost group had greater effect on increasing the PSV(<i>WMD</i>=2.40, 95%<i>CI</i>: 2.12-2.68, <i>P</i><0.00001; <i>WMD</i>=3.76, 95%<i>CI</i>: 3.30-4.22, <i>P</i><0.00001)and the EDV(<i>WMD</i>=0.81, 95%<i>CI</i>: 0.70-0.91, <i>P</i><0.00001; <i>WMD</i>=0.90, 95%<i>CI</i>: 0.72-1.09, <i>P</i><0.00001)of the CRA and the PCA as well as on decreasing the RI(<i>WMD</i>=-0.07, 95%<i>CI</i>: -0.10 to -0.04, <i>P</i><0.00001; <i>WMD</i>=-0.07, 95%<i>CI</i>: -0.08 to -0.05, <i>P</i><0.00001)of the CRA and the PCA; Travoprost was more effective in decreasing astigmatism(<i>WMD</i>=-1.34, 95%<i>CI</i>: -1.62 to -1.06, <i>P</i><0.00001); Compared with timolol, travoprost could significantly decrease the plasma ET-1(<i>WMD</i>=-5.14, 95%<i>CI</i>: -7.08 to -3.20, <i>P</i><0.00001)and the serum MMP(<i>WMD</i>=-12.48, 95%<i>CI</i>: -24.27 to -0.69, <i>P</i>=0.04), while no statistically significant differences were found in the TIMP-2 of the aqueous humor(<i>WMD</i>=-1.40, 95%<i>CI</i>: -5.51-2.71, <i>P</i>=0.51)and the serum TIMP-2(<i>WMD</i>=1.69, 95%<i>CI</i>: -30.03-33.41, <i>P</i>=0.92).CONCLUSION:Compared with timolol, travoprost was more effective in improving hemodynamic indexes and decreasing astigmatism in the treatment of POAG.

Long-Term Effectiveness and Safety of Tafluprost, Travoprost, and Latanoprost in Korean Patients with Primary Open-Angle Glaucoma or Normal-Tension Glaucoma: A Multicenter Retrospective Cohort Study (LOTUS Study).

This multicenter retrospective cohort study compared the effectiveness and safety of long-term tafluprost, travoprost, or latanoprost in patients with primary open-angle glaucoma (POAG) or normal-tension glaucoma (NTG). Data were extracted from electronic medical records of 300 patients treated with tafluprost, travoprost, or latanoprost for >6 months. Propensity matching for age and sex was used for effectiveness and safety comparisons. The primary endpoint was visual field (VF) progression via mean deviation (MD) slope. Secondary endpoints were change of MD, intraocular pressure, pattern standard deviation, VF index, and advanced glaucoma intervention study score. Treatment-related adverse events (AEs) were also compared between groups. Overall, 216 POAG or NTG patients were matched into Match Set 1 (72 patients/group), and 177 NTG-only patients in Match Set 2 (59 patients/group) according to: age (mean: 61, 62 years) and sex (male: 53, 56%). There were no statistically significant between-group differences regarding MD slope (p = 0.413, p = 0.374 in Match Sets 1 and 2, respectively). There were no significant between-group differences/tendencies regarding secondary endpoints. No AEs were serious, and there were no significant between-group differences regarding reported AEs. In patients with POAG or NTG, long-term tafluprost, travoprost, or latanoprost showed similar effects. All three prostaglandin analogs had good long-term safety profiles.

Headaches related to latanoprost in open-angle glaucoma.

Clinical relevance: The existing notion that topical latanoprost can lead to symptoms of headaches by reporting three cases of headache symptoms that developed following instillation of latanoprost prescribed as first-line therapy for newly diagnosed primary open-angle glaucoma (POAG) is explored in this case series.Background: Prostaglandin analogues (PGAs) are often used as first-line treatment in the treatment of POAG. An uncommon and infrequently reported side effect of PGAs is headaches.Methods: A retrospective review of patient records was conducted on patients seen at the Centre for Eye Health between April 2016 and August 2017. Clinical findings, including outcomes following interventions such a punctal occlusion, as well as the proposed pharmacological mechanism underlying this phenomenon are presented and discussed.Results: Case 1 is a 62-year-old Caucasian male diagnosed with POAG and prescribed latanoprost in both eyes. At the follow-up visit, he reported waking up in with a dull throbbing headache following instillation of the eye drops the night before. Case 2 is a 58-year-old Asian male with POAG prescribed latanoprost to both eyes. Within a week, he developed symptoms of recurrent progressively worsening headaches post-instillation which persisted into the morning. Case 3 is a 75-year-old Caucasian male with POAG prescribed latanoprost for both eyes. He developed latanoprost sensitivity as well as headache symptoms associated with the eye drops which resolved followed its cessation. All patients reported initial symptoms of headaches associated with latanoprost use however the headaches were not persistent with intermittent punctal occlusion (cases 1 and 2) or intra-class drug rechallenge (case 3).Conclusion: Although there may be a yet-undiscovered link between a headache response and latanoprost, these cases call to question the pharmacological relationship between latanoprost and headache symptoms. A systemic approach to critically examine the pathophysiological link between pharmacological therapy and potential adverse effects is proposed.

Comparison between Latanoprost, Travoprost, and Tafluprost in reducing intraocular pressure fluctuations in patients with glaucoma.

PURPOSE: To compare the efficacies of latanoprost 0.005%, travoprost 0.004%, and tafluprost 0.0015% in reducing diurnal intraocular pressure (IOP) fluctuations in patients with newly diagnosed primary open-angle glaucoma (POAG). METHODS: In this prospective randomized clinical trial, 60 patients who were newly diagnosed with POAG were divided into three equal groups. Patients were examined at presentation and at second and sixth weeks. Diurnal phasing of IOP was conducted using a calibrated Goldmann applanation tonometer. IOP measurements were recorded from 8:00 am to 9:00 am, from 3:00 pm to 4:00 pm, and from 7:00 pm to 8:00 pm. RESULTS: The study groups were distributed similarly in terms of age and gender (p-values: 0.76) and the participants had a mean age of 52.98 ± 13.43 years. The IOP at the day of inclusion was not statistically significant among the three groups (p-values 0.27, 0.51, and 0.64 at 8 am, 2 pm, and 8 pm, respectively). Similar nonsignificant differences were noticed on the follow-up visits. However, the tafluprost group showed a significant reduction in IOP on the follow-up visit at the second week at 8 pm (30.5% reduction, p-value: 0.03). All three drugs showed a comparable and significant reduction in IOP and IOP fluctuations. The pattern of side effects was similar in all the groups. CONCLUSION: Latanoprost, travoprost, and tafluprost show a similar effectiveness in reducing the mean IOP and the diurnal IOP fluctuation in POAG. Importantly, the three drugs have comparable tolerability with insignificant differences regarding the pattern of their side effects.

Development of IKATP Ion Channel Blockers Targeting Sulfonylurea Resistant Mutant KIR6.2 Based Channels for Treating DEND Syndrome.

Introduction: DEND syndrome is a rare channelopathy characterized by a combination of developmental delay, epilepsy and severe neonatal diabetes. Gain of function mutations in the KCNJ11 gene, encoding the KIR6.2 subunit of the IKATP potassium channel, stand at the basis of most forms of DEND syndrome. In a previous search for existing drugs with the potential of targeting Cantú Syndrome, also resulting from increased IKATP, we found a set of candidate drugs that may also possess the potential to target DEND syndrome. In the current work, we combined Molecular Modelling including Molecular Dynamics simulations, with single cell patch clamp electrophysiology, in order to test the effect of selected drug candidates on the KIR6.2 WT and DEND mutant channels. Methods: Molecular dynamics simulations were performed to investigate potential drug binding sites. To conduct in vitro studies, KIR6.2 Q52R and L164P mutants were constructed. Inside/out patch clamp electrophysiology on transiently transfected HEK293T cells was performed for establishing drug-channel inhibition relationships. Results: Molecular Dynamics simulations provided insight in potential channel interaction and shed light on possible mechanisms of action of the tested drug candidates. Effective IKIR6.2/SUR2a inhibition was obtained with the pore-blocker betaxolol (IC50 values 27-37 µM). Levobetaxolol effectively inhibited WT and L164P (IC50 values 22 µM) and Q52R (IC50 55 µM) channels. Of the SUR binding prostaglandin series, travoprost was found to be the best blocker of WT and L164P channels (IC50 2-3 µM), while Q52R inhibition was 15-20% at 10 µM. Conclusion: Our combination of MD and inside-out electrophysiology provides the rationale for drug mediated IKATP inhibition, and will be the basis for 1) screening of additional existing drugs for repurposing to address DEND syndrome, and 2) rationalized medicinal chemistry to improve IKATP inhibitor efficacy and specificity.

Comparison of the effectiveness and safety of travoprost and latanoprost for the management of open-angle glaucoma given as an evening dose.

As intraocular pressure (IOP) is primarily higher in the morning, an evening dose of prostaglandin analogs is typically used as monotherapy to decrease IOP in patients with open-angle glaucoma. Travoprost (TV) has reported efficacy in treating open-angle glaucoma; however, the safety and efficacy may be different compared with that for latanoprost (LT). The aim of the present study was to compare the effectiveness and safety of an evening dose of TV compared with that of LT in treating open-angle glaucoma. Data including IOP, results of lid and slit-lamp examination and ophthalmoscopy, as well as adverse effects in 250 affected eyes from patients with open-angle glaucoma who received either TV (n=89) or LT (n=161) once in the evening for 3-months were included in the analyses. At the end of treatment, TV (23.45±1.52 vs. 19.15±1.01 mmHg; P<0.0001) and LT (23.93±2.11 vs. 19.45±1.11 mmHg; P<0.0001) successfully lowered the IOP. In addition, there was no significant difference in the reduction of IOP values at the end of treatment between the two groups (P=0.120). Furthermore, there were no adverse effects on visual acuity (P>0.05), except for non-visual acuity, for example hyperemia (P<0.0001 for both groups), while there was a significant increase in the number of patients with dry eyes receiving TV (P=0.020) and a significant increase with eyelid swelling (P=0.036) and headache (P=0.037) in patients receiving LT. In conclusion, evening doses of TV and LT had the same efficacy and manageable adverse effects in the treatment of open-angle glaucoma (level of evidence, 3).