NCX 1741, a Novel Nitric Oxide-Donating Phosphodiesterase-5 Inhibitor, Exerts Rapid and Long-Lasting Intraocular Pressure-Lowering in Cynomolgus Monkeys.

Purpose: We studied the IOP-lowering effects of NCX 1741, a novel nitric oxide (NO)-donating derivative of the phosphodiesterase type-5 inhibitor, avanafil, in Cynomolgus monkey with laser-induced ocular hypertension (OHT-monkeys). NCX 1193 (NO-donating moiety), NCX 1744 (NCX 1741 without ester nitrate moiety), and travoprost (PGF2α analogue) were used for comparison. Ocular exposure after NCX 1741 dosing also was addressed. Methods: Vehicle (phosphate buffer pH 6.0, Kolliphor® 5%, DMSO 0.3%, benzalkonium chloride 0.02%), NCX 1741, NCX 1193, NCX 1744, or travoprost were instilled (30 µL; single dose) masked and conscious IOPs were measured by pneumatonometry. LC-MS/MS-based methods were employed to monitor ocular exposure of NCX 1741 and main metabolites after ocular dosing in New Zealand White rabbits. Results: NCX 1741 (2.2%, 0.8 µmol/eye) lowered IOP with an Emax (ΔΔIOP, IOP change vs. pre-dose and vehicle) between 5 and 8 h post-dosing (ΔΔIOP5h, -5.3 ± 2.0 mmHg and ΔΔIOP8h, -6.0 ± 2.1 mmHg). Conversely, equimolar (0.47%, 0.8 µmol/eye) NCX 1193 IOP-lowering effects were maximal 3 h post-dosing (ΔΔIOP3h, -4.7 ± 1.6 mmHg) and declined thereafter (ΔΔIOP5h, -1.6 ± 1.1 mmHg). In a follow-up study, NCX 1741 (1.5%, 0.5 µmol/eye) was more effective than NCX 1744 despite a similar duration. Further, NCX 1741 was as effective as travoprost (0.1%, 0.06 µmol/eye) at 5 and 8 h post-dosing (travoprost, ΔΔIOP5h, -3.4 ± 2.2 mmHg and ΔΔIOP8h, -4.9 ± 1.3 mmHg) but had shorter duration (NCX 1741, ΔΔIOP24h, -1.5 ± 1.1 mmHg; travoprost, ΔΔIOP24h, -7.1 ± 2.8 mmHg). NCX 1741 resulted in significant aqueous humor exposure, as determined by the levels of the main metabolite, avanafil. Conclusions: NCX 1741 rapidly and effectively lowers IOP in OHT-monkeys for several hours post-dosing. How these effects translate in humans is still to be defined.

Nanoemulsion as a feasible and biocompatible carrier for ocular delivery of travoprost: Improved pharmacokinetic/pharmacodynamic properties.

Travoprost is a synthetic prostaglandin F2α analogue used in treatment of glaucoma. Due to its water insolubility and oily nature, novel delivery systems need to be developed to enhance its bioavailability, and sustain its release. In the current work, travoprost nanoemulsion was explored as a novel carrier prepared using low energy technique. Results showed that travoprost nanoemulsions exhibited suitable nanodroplet size, zeta potential, pH, refractive index, controlled release, as well as sufficient stability under accelerated conditions. In vivo studies delineated the enhanced absorption of travoprost nanoemulsion compared to the marketed eye drops Travatan®, as proven by the higher Cmax and AUC of the former, and its prolonged intraocular pressure reduction time. Moreover, the nanoemulsion formulation was proven safe and non-irritant to ocular surfaces. Therefore, it can be suggested that travoprost nanoemulsion is a promising ocular delivery system for glaucoma treatment.

The efficacy of the fixed combination of latanoprost and timolol versus other fixed combinations for primary open-angle glaucoma and ocular hypertension: A systematic review and meta-analysis.

BACKGROUND: Fixed-combination (FC) therapy is used in primary open-angle glaucoma (POAG) and ocular hypertension (OHT) patients who require more than one medication to reach their target intraocular pressure (IOP). Currently, there are several FC therapies available for the treatment of glaucoma. The FC of latanoprost/timolol (LTFC) is a commonly used FC. Here, we conducted systematic review to compare the IOP-lowering effects of LTFC with other FCs for patients with POAG and OHT. MATERIALS AND METHODS: We searched PubMed, EMBASE, the Cochrane Library, and Web of Science for randomized-controlled clinical trials and cross-over studies. The outcomes were mean IOP and IOP fluctuation after one month of treatment. Meta-analysis was carried out using RevMan (version 5.1) software. After conducting meta-analyses, we rated the quality of each meta-analysis as high, moderate, low, or very low using the "GRADE" system. RESULTS: We included 16 trials in this meta-analysis. Moderate-quality meta-analysis showed that LTFC had a comparable mean IOP to that of a fixed combination of travoprost and timolol (TTFC) [mean difference (MD): 0.07 mmHg] and a fixed combination of dorzolamide and timolol (DTFC) [MD: -0.31 mmHg], and it also had a comparable IOP-fluctuation effect compared to that of TTFC [MD: 0.13 mm Hg] and DTFC [MD: 0.25 mmHg]. Compared to the fixed combination of bimatoprost and timolol (BiTFC), moderate-quality evidence showed a higher mean IOP in the LTFC group [MD 0.76 mmHg], whereas low-quality meta-analysis showed higher IOP fluctuation [MD 1.09 mmHg] in the LTFC group. CONCLUSIONS: LTFC is as effective as TTFC and DTFC, but worse than BiTFC in controlling mean IOP and IOP fluctuation for POAG or OHT patients. The quality of our meta-analyses was assessed as moderate, with the exception of one low-quality analysis that compared the IOP fluctuation of LTFC and BiTFC.

Ocular Surface Disease with BAK preserved Travoprost and Polyquaternium 1(Polyquad) preserved Travoprost.

Introduction. The topical medications containing benzalkonium chloride (BAK) as preservative is known to induce corneal toxicity and ocular surface disease (OSD) in glaucoma patients. Newer preservatives like SofZia or polyquaternium-1 (Polyquad) have been developed to replace BAK in many medications. The present study aimed at comparing the OSD in glaucoma patients receiving BAK preserved travoprost versus travoprost with polyquad as preservative and controls not receiving any medications. Methods. This prospective, controlled, observational study was conducted on patients of primary open angle glaucoma (POAG) on medications for more than 6 months. The first group comprised of 40 patients receiving BAK preserved travoprost, the second group included 40 patients receiving polyquad preserved travoprost and 30 of control group not receiving any medical treatment. Ocular Surface Disease Index (OSDI) scores using Ocular Surface Disease Index (OSDI) Questionnaire were assessed and compared in all subjects. Results. The mean OSDI score was 29.09 ± 13.45 in BAK group, 12.4 ± 5.085 in polyquad group and 10.93 ± 7.36 in controls. The mean difference in OSDI scores between BAK and polyquad group 16.63 (p < 0.05) and between the BAK and control group was 18.96 (p < 0.05). The mean difference in OSDI scores between the polyquad and control group was 1.53 (p > 0.05). The mean IOP in the BAK group was 19.2 ± 3.5 and in polyquad group was 20.1 ± 4.2. The IOP measured at 12 months of treatment was 13.2 ± 2.1 in BAK group and 12.8 ± 3.3 in polyquad group. The IOP measured at baseline and 12 months showed statistically significant difference in both the groups (p

Randomized crossover trial comparing effectiveness and tolerability of generic and brand-name travoprost.

OBJECTIVE: The primary goal is to determine if the intraocular pressure reducing effect of generic Sandoz travoprost is equivalent to that of brand-name Travatan Z. The secondary goal is to determine if generic Sandoz travoprost is as well tolerated as Travatan Z. METHODS: This prospective randomized crossover trial allocated 76 patients with primary open-angle glaucoma, normotensive glaucoma, or ocular hypertension in a 1:1 ratio to start with either generic Sandoz travoprost or Travatan Z. Crossover happened after 3 weeks. The primary endpoint, intraocular pressure, was measured in both eyes at baseline, at week 3, and at week 6. The secondary endpoint was tolerability of both drugs as assessed by a questionnaire administered at week 3 and week 6. RESULTS: The intraocular pressure lowering effect of generic Sandoz travoprost was equivalent to that of Travatan Z (18.20 ± 3.41 mmHg and 18.44 ± 3.48 mmHg respectively, p < 0.0001). Tolerability, as measured with a questionnaire, was similar between the two formulations of travoprost. CONCLUSION: This study is the first to compare a brand-name travoprost with one of its generic forms and adds to the body of evidence that generic glaucoma eye drops are as effective and well-tolerated as their brand name counterparts. The intraocular pressure lowering effect of generic Sandoz travoprost is equivalent to that of Travatan Z. Patient tolerance of generic and brand-name travoprost is similar.

Effect of Topical Hypotensive Medications for Preventing Intraocular Pressure Increase after Cataract Surgery in Eyes with Glaucoma.

PURPOSE: To compare the effects of a topical intraocular pressure (IOP)-lowering medication for preventing an IOP increase after cataract surgery in eyes with glaucoma. DESIGN: Randomized clinical study. METHODS: A total of 165 eyes of 165 patients with primary open-angle glaucoma or pseudoexfoliation glaucoma scheduled for phacoemulsification were randomly assigned to 1 of 3 groups to receive each medication immediately postoperatively: 1) prostaglandin F2α analog (travoprost), 2) ß-blocker (timolol maleate), or 3) carbonic anhydrase inhibitor (brinzolamide). Intraocular pressure (IOP) was measured using a rebound tonometer at 1 hour preoperatively, at the end of surgery, and at 2, 4, 6, 8, and 24 hours postoperatively. The incidence of eyes exhibiting a marked IOP increase to greater than 25 mm Hg was compared among the groups. RESULTS: At 1 hour preoperatively and at the end of surgery, mean IOP did not differ significantly among the groups. Mean IOP increased significantly between 4 and 8 hours postoperatively and then decreased at 24 hours postoperatively in all groups (P < .0001). Mean IOP was significantly lower in the brinzolamide group than in the travoprost or timolol group at 4, 6, and 8 hours postoperatively (P ≤ .0374) and did not differ significantly among groups at 2 and 24 hours postoperatively. The incidence of an IOP spike was significantly lower in the brinzolamide group than in the travoprost and timolol groups (P = .0029). CONCLUSIONS: Brinzolamide reduces the short-term IOP increase after cataract surgery more effectively than travoprost or timolol in eyes with glaucoma, suggesting that brinzolamide is preferable for preventing an IOP spike.

15 keto fluprostenol isopropyl ester (80 µgr/mL) gel for cosmetic eyelash growth and enhancement.

BACKGROUND: Eyelashes have both a protective and an aesthetic function. Hypotrichosis of the eyelashes may negatively influence an individual's self-perception. OBJECTIVE: To evaluate efficacy and safety of topical administration of a new cosmetic preparation containing 15 keto fluprostenol isopropyl ester (80 µgr/mL) for the treatment of idiopathic hypotrichosis of the eyelashes. METHODS: This is a monocentric, double-blind, vehicle-controlled study. Forty patients (18 years) with idiopathic hypotrichosis (GEA 1 or 2), who also exhibit feelings of low confidence, based on the ESQ score, were divided into two groups. Group 1: twenty women treated with once-daily 15 keto fluprostenol isopropyl ester gel and Group 2: twenty women treated only with the vehicle gel. RESULTS: Group 1: The average difference in eyelash length measured at the midpoint of palpebral margins between T0 and T2 for Group 1 was 1633 mm and for Group B was 0.25 (P < 0.0001). Comparing the ESQ questionnaires of Groups 1 and 2 from T0 to T2, only the 80% of the patients of Group 1 declared to dedicate less time to the application of cosmetic mascara, having longer and darker lashes at T2 vs patients of Group 2, of which only 20% reported longer and darker eyelashes at T2. About safety, only one patient of Group 1 experienced sensation of ocular sensation heaviness and headache. No other side effects were referred. CONCLUSIONS: 15 keto fluprostenol isopropyl ester gel was effective in enhancing eyelash growth, with an excellent safety profile.

Reversal of retinal pigment epithelial detachment after cessation of topical travoprost therapy.

PURPOSE: To report the rare incidence of retinal pigment epithelial detachment (RPED) followed by topical travoprost therapy and its subsequent reattachment after cessation of the drug. METHODS: A 60-year-old male presented with gradual loss of vision in both eyes and distorted images in right eye. He gave a history of visiting an ophthalmologist a week ago for a routine eye examination. His previous reports revealed best-corrected visual acuity (BCVA) of 6/6, N6 in both eyes with raised intraocular pressures. A diagnosis of primary open-angle glaucoma was made and prescribed topical travoprost 0.004% eye drops. This patient's subsequent visit with diagnosis and treatment is mentioned in this case report. RESULTS: On examination, his BCVA was found to be 6/36, N12 and 6/6, N6 in right and left eyes, respectively. Optical coherence tomography (OCT) macular scan revealed RPED involving fovea in the right eye and inferotemporal to fovea in the left eye. Patient was advised to discontinue topical travoprost and started brinzolamide 1% eye drops. Ten-day follow-up visit revealed partially resolved RPED by OCT with 6/9 and 6/6 visual acuity in the right and left eyes, respectively. After 1 month, reversal of RPED was noted in OCT with 6/6 vision in both eyes. CONCLUSION: Hence, clinicians should be aware of this rare incidence of RPED followed by travoprost therapy. First case of RPED following travoprost therapy and complete reattachment upon withdrawal is reported here in this case report.

Association of Postoperative Topical Prostaglandin Analog or Beta-Blocker Use and Incidence of Pseudophakic Cystoid Macular Edema.

PURPOSE: The purpose of this article is to determine the association of postoperative topical prostaglandin analog (PGA) or topical beta-blocker use and the incidence of pseudophakic cystoid macular edema (CME). METHODS: This was a nested case-control study. All adult patients who underwent cataract surgery between January 1, 2006 and December 31, 2016 and who were enrolled in the PharMetrics Plus database were eligible for inclusion. The association between postoperative topical PGAs (bimatoprost, latanoprost, and travoprost/travoprost-z) or beta-blocker (betaxolol, levobunolol, and timolol) use and the incidence of pseudophakic CME was assessed by conditional logistic regression. RESULTS: Five hundred eight cases and 5080 controls were included in the analyses. Incidence of pseudophakic CME was found to be statistically significantly associated with the current postoperative use of both topical PGAs [relative risk (RR), 1.86; 95% confidence interval (CI), 1.04-3.32] and topical beta-blockers (RR, 2.64; 95% CI, 1.08-6.49). Postoperative use of each of bimatoprost (RR, 2.73; 95% CI, 1.35%-5.53%) and travoprost/travoprost-z (RR, 3.16; 95% CI, 1.42-7.03) in the year before diagnosis was demonstrated to be statistically significantly associated with the incidence of pseudophakic CME. This association was not observed to be statistically significant with the postoperative use of latanoprost (RR, 1.55; 95% CI, 0.84-2.88). CONCLUSIONS: To the best of our knowledge this is the largest study that has investigated the association between postoperative topical PGA or topical beta-blocker use and the incidence of pseudophakic CME. Postoperative use of both topical PGAs and topical beta-blockers was found to be associated with the incidence of pseudophakic CME.

Meibomian Gland Features and Conjunctival Goblet Cell Density in Glaucomatous Patients Controlled With Prostaglandin/Timolol Fixed Combinations: A Case Control, Cross-sectional Study.

PURPOSE: To investigate, using in vivo confocal microscopy (IVCM), the Meibomian gland (MG) features and conjunctival goblet cell density (GCD) in glaucomatous patients controlled with prostaglandin/timolol fixed combinations (PTFCs). MATERIALS AND METHODS: In this cross-sectional study, 60 white patients were treated with PTFCs, 15 with latanoprost+timolol (L+T) unfixed combination, and 15 controls were enrolled. Patients underwent the Ocular Surface Disease Index questionnaire, tear film breakup time, corneal staining, Schirmer test I, and IVCM of MGs and goblet cells. The main outcome measures were: mean Meibomian acinar density (MMAD) and area (MMAA), inhomogeneity of glandular interstice (InI) and acinar wall (InAW), and GCD. RESULTS: PTFCs were: latanoprost/timolol (LTFC, 15 eyes), travoprost/timolol (TTFC, 15), bimatoprost/timolol (BTFC, 15), and preservative-free bimatoprost/timolol (PF-BTFC, 15) fixed combinations. Mean time on therapy did not differ among treatments. IVCM documented lower GCD, MMAD, and MMAA (P<0.001), and greater InI and InAW (P<0.05) in glaucoma patients compared with controls. L+T showed worse values compared with PTFCs and PF-BTFC (P<0.05). Preserved PTFCs showed lower MMAD, MMAA, GCD, and greater InI and InAW compared with PF-BTFC (P<0.05) and controls (P<0.001). Differences were not found among PTFCs. InI and InAW significantly correlated with Ocular Surface Disease Index and breakup time (P<0.001), corneal staining (P<0.05), and GCD (P<0.001); GCD correlated with MMAD (P<0.05). CONCLUSIONS: PTFCs were less toxic towards MGs and goblet cells compared with the L+T unfixed combination, with PF-BTFC presenting the most tolerated profile. These findings should be carefully considered given the role of these structures in the induction of the glaucoma-related ocular surface disease.

The efficacy and safety of bimatoprost/timolol maleate, latanoprost/timolol maleate, and travoprost/timolol maleate fixed combinations on 24-h IOP.

PURPOSE: To evaluate the effect of bimatoprost/timolol maleate fixed combination (BTFC), latanoprost/timolol maleate fixed combination (LTFC), and travoprost/timolol maleate fixed combination (TTFC) on 24-h intraocular pressure (IOP) in patients with open-angle glaucoma. METHODS: This prospective, observer-masked, randomized study included 50 patients with primary open-angle glaucoma. All patients were using hypotensive lipids and timolol maleate fixed combination treatment for ≥4 weeks and had an IOP ≤ 21 mmHg. Group 1 (n = 18) received BTFC, group 2 (n = 14) received LTFC, and group 3 (n = 18) received TTFC. All patients were hospitalized, and IOP was monitored for 24-h (10:00, 14:00, 18:00, 22:00, 02:00, and 06:00). Mean diurnal IOP variation measurements were taken between 06:00 and 18:00, and mean nocturnal IOP variation measurements were taken between 22:00 and 02:00. Mean IOP and IOP variation in the three groups were compared. RESULTS: Mean 24-h IOP did not differ significantly between the three groups (group 1: 14.6 ± 2.9 mmHg; group 2: 14.1 ± 3.7 mmHg and group 3: 15.8 ± 2.0 mmHg; P > 0.05). Mean diurnal IOP variation was 4.6 ± 2.3 mmHg in group 1, 5.8 ± 2.4 mmHg in group 2, and 4.3 ± 1.7 mmHg in group 3, and mean nocturnal IOP variation was 3.2 ± 2.8 mmHg in group 1, 2.9 ± 1.9 mmHg in group 2, and 3.0 ± 1.6 mmHg group 3. There were not any significant differences in diurnal or nocturnal IOP variation between the three groups (P < 0.05). CONCLUSION: All three fixed combinations effectively controlled IOP for 24-h and had a similar effect on diurnal and nocturnal IOP variations.

Periorbital Changes associated with Topical Prostaglandins Analogues in a Hispanic Population.

OBJECTIVE: To describe the prevalent side effects of prostaglandin analogues (PA) in a Hispanic population and their effect on quality of life (QOL). PATIENTS AND METHODS: This is a cross-sectional study conducted in a tertiary medical facility in which patients were evaluated in a single visit. Total of 14 participants in the study, 10 women and 4 men. Ages ranged from 26-78 years old. Subjects underwent a single full Oculoplastic evaluation by two physicians; one was blinded on patient medical history and assessed for PA side effects. After evaluation, each study subject was asked to answer a self reported QOL questionnaire. RESULTS: Study participants had used or were currently using Bimatoprost (28.6%), Latanoprost (50%) or Travoprost (21.4%). After evaluate periorbital changes, 2 patients (14.3%) had ptosis, 2 (14.3%) had periorbital skin hyperpigmentation, 11 (78.6%) had periorbital fat show, 11 (78.6%) had eyelash elongation, 1 (7.1%) had injected conjunctiva, 5 (35.7%) had iris hyperpigmentation. 10 (71.4%) noted changes in the size/shape of their eyes. The questionnaire show that 10 (71.4%) disliked how their eyes looked. 9 (62.4%) reported dry eyes, 3 (21.4%) noted increased need to blink, 5 (35.7%) reported foreign body sensation, 7 (50%) reported burning sensation, 2 (14.2%) reported secretions and 3 (21.4%) reported sticky eyes. Mean QOL was 3.50, 2.14, and 2.00 in the Bimatroprost, Latanoprost, and Travoprost users respectively. CONCLUSION: QOL questionnaire showed that Bimatoprost side effects had the most negative impact in QOL, followed by the Latanoprost and Travoprost groups.

Periorbital changes associated with prostaglandin analogs in Korean patients.

BACKGROUND: Prostaglandin analogs (PGAs) are commonly used to treat glaucoma because of their powerful intraocular pressure lowering effect. However, various periorbital changes associated with the use of PGAs have been reported. We investigated the incidence of periorbital changes in Korean patients who were treated with PGAs, and analyzed clinical factors associated with superior sulcus deepening. METHODS: This study included 58 glaucoma patients who were treated with latanoprost, travoprost, or bimatoprost unilaterally. Face photographs were collected, and periorbital changes such as superior sulcus deepening, eyelid pigmentation, ptosis, lid retraction, dermatochalasis, and redness were evaluated by two oculoplastic specialists. For each patient, the contralateral eye served as a control. The frequency of ptosis, dermatochalasis, pigmentation, erythema, and superior sulcus deepening were analyzed. Demographic and ocular factors were compared between patients who showed superior sulcus deepening and those who did not. RESULTS: Thirty-one patients (53.4%) showed one or more periorbital changes associated with PGAs. The most common change was superior sulcus deepening (24.1%), followed by eyelid pigmentation (19.0%), eyelid erythema (19.0%), dermatochalasis (10.3%), eyelid retraction (5.2%), and ptosis (3.4%). The age of the patient and the duration of PGA administration was significantly correlated with superior sulcus deepening (p = 0.007, p = 0.002, respectively). CONCLUSIONS: Periorbital changes are frequently seen in patients who use PGAs, and superior sulcus deepening is the most common change in Korean patients. Long-term use of PGAs and old age were associated with superior sulcus deepening.

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

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

Pharmacokinetics and Safety of Travoprost 0.004% Ophthalmic Solution Preserved with Polyquad in Pediatric Patients with Glaucoma.

PURPOSE: To evaluate the systemic pharmacokinetics (PKs) of travoprost 0.004% preserved with Polyquad® (TRAVATAN®) in pediatric patients with glaucoma or ocular hypertension. METHODS: This was a phase 1, open-label, multicenter clinical study of patients aged ≥2 months to <18 years. Patients received daily administration of travoprost 0.004% preserved with Polyquad in both eyes for 7 days. Plasma samples were collected 30 min before the final dose and at 10, 20, 40, and 80 min postdose. The main outcome measure was maximum concentration of travoprost free acid in plasma (Cmax). RESULTS: Included in the PK analysis were 24 patients (average age 9.6 ± 4.9 years). At least 1 sample with quantifiable levels of travoprost free acid was collected for 11 patients. The mean Cmax was 0.0471 ± 0.0105 ng/mL for patients aged 2 months to <3 years; 0.0258 ± 0.0128 ng/mL for ages 3 to <12 years; and 0.0109 ± 0.0005 ng/mL for ages 12 to <18 years. Travoprost was undetectable in samples collected predose from pediatric patients. Treatment-related adverse events (AEs) included hyperemia, eye pain, and eye pruritus (n = 1 each). There were no discontinuations or drug-related serious AEs. CONCLUSIONS: Travoprost free acid concentration in plasma was low in pediatric patients, detectable in only 11 of 24 patients. There was no accumulation of travoprost over the course of treatment. No clear relationship was observed between age/body surface area and Cmax. No increased risk was identified for the use of travoprost 0.004% preserved with Polyquad in patients <18 years of age.

Implantation of two second-generation trabecular micro-bypass stents and topical travoprost in open-angle glaucoma not controlled on two preoperative medications: 18-month follow-up.

IMPORTANCE: Additional data are sought regarding treatment options for glaucoma, a major cause of global blindness. BACKGROUND: The study assessed outcomes following standalone implantation of two second-generation trabecular micro-bypass stents and postoperative topical prostaglandin in eyes with open-angle glaucoma not controlled on two preoperative medications. DESIGN: The study design is a prospective, nonrandomized, open-label study at a tertiary-care ophthalmology centre. PARTICIPANTS: Subjects had open-angle glaucoma with preoperative intraocular pressure of 18-30 mmHg on two medications, a medication washout phase, and post-washout intraocular pressure of 22-38 mmHg. All subjects (N = 53) have been followed for 18 months. METHODS: One day following implantation of two second-generation trabecular micro-bypass stents, subjects started topical travoprost. Medication washout was repeated at month 12. MAIN OUTCOME MEASURES: The main outcome measure was the proportion of eyes with intraocular pressure reduction ≥ 20% versus medicated baseline intraocular pressure with reduction of one medication at 12 months. RESULTS: At 12 months, 91% of eyes achieved intraocular pressure reduction ≥ 20% with reduction of one medication. All eyes had intraocular pressure ≤ 18 mmHg with reduction of one medication, and 87% had intraocular pressure ≤ 15 mmHg. Mean intraocular pressure on one medication was ≤ 13.0 mmHg (≥ 34% reduction) through 18 months. Mean post-washout intraocular pressure at month 13 was 33% lower than preoperative unmedicated intraocular pressure. No adverse events occurred through 18 months. CONCLUSIONS AND RELEVANCE: In open-angle glaucoma eyes on two preoperative medications, treatment with two second-generation trabecular stents and one postoperative prostaglandin resulted in mean intraocular pressure ≤ 13 mmHg with reduction of one medication, with favourable safety. These findings show the utility of second-generation trabecular bypass with postoperative prostaglandin in patients with open-angle glaucoma.

Topical medication instillation techniques for glaucoma.

BACKGROUND: Glaucoma is a leading cause of irreversible blindness worldwide and the second most common cause of blindness after cataracts. The primary treatment for glaucoma aims to lower intraocular pressure (IOP) with the use of topical medicines. Topical medication instillation techniques, such as eyelid closure and nasolacrimal occlusion when instilling drops, have been proposed as potential methods to increase ocular absorption and decrease systemic absorption of the drops. OBJECTIVES: To investigate the effectiveness of topical medication instillation techniques compared with usual care or another method of instillation of topical medication in the management of glaucoma or ocular hypertension. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 12), MEDLINE Ovid (1946 to 8 December 2016), Embase Ovid (1947 to 8 December 2016), PubMed (1948 to 8 December 2016), LILACS (Latin American and Caribbean Health Sciences Literature Database) (1982 to 8 December 2016), International Pharmaceutical Abstracts Database (1970 to 8 December 2016), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) (last searched 13 May 2013), ClinicalTrials.gov (www.clinicaltrials.gov) (searched 8 December 2016) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en) (searched 8 December 2016). We did not use any date or language restrictions in the electronic searches for trials. SELECTION CRITERIA: We included randomized controlled trials which had compared any topical medication instillation technique with usual care or a different method of instillation of topical medication. DATA COLLECTION AND ANALYSIS: Two review authors independently screened records from the searches for eligibility, assessed the risk of bias, and extracted data. We followed methods recommended by Cochrane. MAIN RESULTS: We identified two trials (122 eyes of 61 participants) that had evaluated a topical medication instillation technique. We also identified two ongoing trials. Both included trials used a within-person design and administered prostaglandin monotherapy for glaucoma or ocular hypertension. Because the trials evaluated different instillation techniques and assessed different outcomes, we performed no meta-analysis.One trial, conducted in the US, evaluated the effect of eyelid closure (one and three minutes) versus no eyelid closure on lowering IOP. At one to two weeks' follow-up, reduction in IOP was similar in the eyelid closure group and the no eyelid closure group (mean difference (MD) -0.33 mmHg, 95% confidence interval (CI) -0.8 to 1.5; 51 participants; moderate-certainty evidence).The second trial, conducted in Italy, evaluated the effect of using an absorbent cloth to wipe excess fluid after instillation (fluid removal) versus not using an absorbent cloth (no removal) on reducing dermatologic adverse events. At four months' follow-up, eyelashes were shorter among eyes in the fluid removal group compared with the no fluid removal group (MD -1.70 mm, 95% CI -3.46 to 0.06; 10 participants; low-certainty evidence). Fewer eyes showed skin hyperpigmentation in the eyelid region towards the nose in the fluid removal group compared with the no removal group (RR 0.07, 95% CI 0.01 to 0.84; 10 participants; low-certainty evidence); however, the difference was uncertain in the eyelid region towards the temples (RR 0.44, 95% CI 0.07 to 2.66; 10 participants; low-certainty evidence). The effect hypertrichosis (excessive hair growth) was uncertain between groups (RR 1.00, 95% CI 0.17 to 5.98; 10 participants; low-certainty evidence).Neither trial reported other outcomes specified for this review, including the proportion of participants with IOP less than 21 mmHg; participant-reported outcomes related to the ease, convenience, and comfort of instillation techniques; physiologic measurements of systemic absorption; escalation of therapy; mean change in visual fields; optic nerve progression; mean change in best-corrected visual acuity; proportion in whom glaucoma developed; quality of life outcomes; or cost-effectiveness outcomes. Neither trial reported data at follow-up times of more than four months. AUTHORS' CONCLUSIONS: Evidence to evaluate the effectiveness of topical medication instillation techniques for treatment of glaucoma is lacking. It is unclear what, if any, effects instillation techniques have on topical medical therapy for glaucoma.

Adherence to Fixed-Combination Versus Unfixed Travoprost 0.004%/Timolol 0.5% for Glaucoma or Ocular Hypertension: A Randomized Trial.

PURPOSE: To assess adherence to treatment with fixed-combination travoprost 0.004%/timolol 0.5% (TTFC) compared with separate containers of travoprost 0.004% and timolol 0.5% (TRAV+TIM; unfixed) using electronic dosing aids. DESIGN: Randomized, controlled, observer-masked clinical trial. METHODS: setting: Two US clinical sites. PATIENT POPULATION: Eligible patients were adults diagnosed with open-angle glaucoma or ocular hypertension. Patients (n = 81) were sequentially randomized 1:1 to receive TTFC or TRAV+TIM for 12 months. INTERVENTION: TTFC was administered once daily in the morning or evening with a single dosing aid. Patients randomized to TRAV+TIM administered TRAV once daily in the evening and TIM once daily in the morning using separate dosing aids. MAIN OUTCOME MEASURE: Adherence with administered medication, as recorded by the dosing aids. RESULTS: Mean ± SD patient age was 60 ± 10 years; most patients were male and white. Compared with TRAV+TIM (n = 40), patients receiving TTFC (n = 41) were consistently adherent on a greater percentage of days through month 12 (60% vs 43%). At months 1, 3, 6, and 12, 80% adherence was achieved by 71% vs 38%, 53% vs 30%, 45% vs 16%, and 32% vs 11% of patients receiving TTFC vs TRAV+TIM, respectively. Significantly more patients were adherent on ≥80% of days with TTFC compared with TRAV+TIM (P < .001 to P = .041). Both treatments reduced IOP from baseline, and no safety issues were identified in either group. Ocular hyperemia was the most common treatment-related adverse event (n = 3/group). CONCLUSIONS: Patients receiving TTFC maintained better treatment adherence compared with patients receiving TRAV+TIM through 12 months of on-therapy evaluation. This suggests that, for patients requiring multiple IOP-lowering medications, a fixed combination may provide improved long-term adherence compared with unfixed therapy.