Conjunctival Bacteria Flora of Glaucoma Patients During Long-Term Administration of Prostaglandin Analog Drops.

Purpose: To investigate the effects of the long-term use of prostaglandin analogs for glaucoma treatment on the indigenous flora of the conjunctiva. Methods: Bacterial isolates were collected from the conjunctival sacs of 68 patients at Miyata Eye Hospital from February to September 2014, who had been receiving continuous monotherapy with prostaglandin analogs for glaucoma for at least 1 year. Minimum inhibitory concentrations of levofloxacin, gatifloxacin, moxifloxacin, cefmenoxime, tobramycin, chloramphenicol, and erythromycin against the isolates were measured to determine susceptibility. Results: The positive culture rate in all cases was 90.5% (57/63 eyes), and a total of 79 bacterial strains were isolated. The isolated bacteria included aerobic gram-positive cocci (8% Staphylococcus aureus and 41% Staphylococcus epidermidis), coagulase-negative staphylococci (5%), Streptococcus spp. (1%), Corynebacterium spp. (4%), gram-negative bacteria (4%), and the facultative anaerobe Propionibacterium acnes (33%). The positive culture rates for patients using 0.005% latanoprost (Xa group) and 0.004% travoprost (Tz group) were 88.9% and 92.6%, respectively, with no statistically significant difference in the composition of isolated bacteria between groups. Methicillin-resistant S. epidermidis (MRSE) was significantly more frequently isolated in the Xa group. The antimicrobial susceptibility rates of S. epidermidis were significantly lower in the Xa group for levofloxacin, gatifloxacin, moxifloxacin, and tobramycin. Conclusions: The indigenous flora may be affected by the long-term use of prostaglandin analogs. The higher incidence of MRSE in the Xa group should be considered during the long-term, continuous administration of eye drops, such as in glaucoma treatment.

Morning dosing of once-daily glaucoma medication is more convenient and may lead to greater adherence than evening dosing.

PURPOSE: To determine if adherence and convenience of once-daily glaucoma medication is greater in the morning or the evening. DESIGN: Prospective, randomized crossover treatment trial. PATIENTS AND METHODS: Thirty patients newly diagnosed with glaucoma or ocular hypertension requiring intraocular pressure (IOP) reduction were started on travoprost eye drops and randomized to either morning or evening administration for 1 month. They were then crossed over to the opposite dosing schedule for the following month. Adherence was monitored using an automated dosing aid. MAIN OUTCOME MEASURES: Adherence was compared between morning versus evening dosing and first versus second month dosing. Demographic characteristics were obtained, treatment effect was measured, and patients completed a post-study questionnaire regarding the convenience of the 2 dosing regimens. RESULTS: Patient adherence overall was good (89.3%). There was no statistically significant difference (P=0.07) in adherence between morning dosing (90.9%) and evening dosing (87.3%). Adherence in the first month (91.7%) was superior to the second month (86.5%). There was no significant difference in IOP response between morning and evening dosing. Patients found morning dosing more convenient than evening dosing. CONCLUSIONS: Early adherence to treatment with a prostaglandin analogue is good, but patients prefer morning administration to evening administration. This may lead to greater adherence with morning administration, particularly among men. Adherence decreases from the first to second month after initiation of treatment. IOP response to this treatment is not significantly affected by morning versus evening administration.

Polyoxyethylene hydrogenated castor oil modulates benzalkonium chloride toxicity: comparison of acute corneal barrier dysfunction induced by travoprost Z and travoprost.

PURPOSE: To determine the element that modulates benzalkonium chloride (BAC) toxicity by using a new electrophysiological method to evaluate acute corneal barrier dysfunction induced by travoprost Z with sofZia (Travatan Z(®)), travoprost with 0.015% BAC (Travatan(®)), and its additives. METHODS: Corneal transepithelial electrical resistance (TER) was measured in live white Japanese rabbits by 2 Ag/AgCl electrodes placed in the anterior aqueous chamber and on the cornea. We evaluated corneal TER changes after a 60-s exposure to travoprost Z, travoprost, and 0.015% BAC. Similarly, TER changes were evaluated after corneas were exposed for 60 s to the travoprost additives ethylenediaminetetraacetic acid disodium salt, boric acid, mannitol, trometamol, and polyoxyethylene hydrogenated castor oil 40 (HCO-40) with or without BAC. Corneal damage was examined after exposure to BAC with or without travoprost additives using scanning electron microscopy (SEM) and a cytotoxicity assay. RESULTS: Although no decreases of TER were noted after exposure to travoprost Z with sofZia and travoprost with 0.015% BAC, a significant decrease of corneal TER was observed after 0.015% BAC exposure. With the exception of BAC, no corneal TER decreases were observed for any travoprost additives. After corneal exposure to travoprost additives with BAC, HCO-40 was able to prevent the BAC-induced TER decrease. SEM observations and the cytotoxicity assay confirmed that there was a remarkable improvement of BAC-induced corneal epithelial toxicity after addition of HCO-40 to the BAC. CONCLUSIONS: Travoprost Z with sofZia and travoprost with BAC do not induce acute corneal barrier dysfunction. HCO-40 provides protection against BAC-induced corneal toxicity.

Effectiveness of ophthalmic solution preservatives: a comparison of latanoprost with 0.02% benzalkonium chloride and travoprost with the sofZia preservative system.

BACKGROUND: Although in vitro and in vivo laboratory studies have suggested that benzalkonium chloride (BAK) in topical ophthalmic solutions may be detrimental to corneal epithelial cells, multiple short- and long-term clinical studies have provided evidence supporting the safety of BAK. Despite the conflicting evidence, BAK is the most commonly used preservative in ophthalmic products largely due to its proven antimicrobial efficacy. This study was designed to characterize the antimicrobial performance of two commonly used topical ocular hypotensive agents that employ different preservative systems: latanoprost 0.005% with 0.02% BAK and travoprost 0.004% with sofZia, a proprietary ionic buffer system. METHODS: Each product was tested for antimicrobial effectiveness by European Pharmacopoeia A (EP-A) standards, the most stringent standards of the three major compendia, which specify two early sampling time points (6 and 24 hours) not required by the United States Pharmacopeia or Japanese Pharmacopoeia. Aliquots were inoculated with between 10(5) and 10(6) colony-forming units of the test organisms: Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Candida albicans and Aspergillus brasiliensis. Sampling and enumeration were conducted at protocol-defined time points through 28 days. RESULTS: BAK-containing latanoprost met EP-A criteria by immediately reducing all bacterial challenge organisms to the test sensitivity and fungal challenges within the first six hours while the preservative activity of travoprost with sofZia did not. Complete bacterial reduction by travoprost with sofZia was not shown until seven days into the test, and fungal reduction never exceeded the requisite 2 logs during the 28-day test. Travoprost with sofZia also did not meet EP-B criteria due to its limited effectiveness against Staphylococcus aureus. Both products satisfied United States and Japanese pharmacopoeial criteria. CONCLUSIONS: Latanoprost with 0.02% BAK exhibited more effective microbial protection than travoprost with sofZia using rates of microbial reduction, time to no recovery for all challenges and evaluation against EP-A criteria as measures. The rapid and complete reduction of all microbial challenges demonstrates that antimicrobial activity of latanoprost with 0.02% BAK exceeds that of travoprost with sofZia preservative system in these products and provides a more protective environment in the event of contamination and subsequent exposure to microorganisms during use.

Immunohistochemical expression of HLA-DR in the conjunctiva of patients under topical prostaglandin analogs treatment.

PURPOSE: Subclinical inflammation may be observed in patients using topical antiglaucomatous drugs. The objective of this study was to investigate inflammation in conjunctiva of glaucoma patients using prostaglandin analogs, by the detection of an immunogenetic marker (HLA-DR) and compare the effect of 3 different drugs: latanoprost, bimatoprost, and travoprost in the induction of this inflammation. SUBJECTS AND METHODS: Thirty-three patients with primary open-angle glaucoma were evaluated without and with prostaglandin analogs topical therapy. Imprints of conjunctival cells were obtained, fixed on glass slides, and prepared for immunohistochemical analysis. RESULTS: Before the use of prostaglandin analogs, 4 of the 33 patients evaluated presented expression of HLA-DR in the conjunctiva (mild). After 1 month on prostaglandin analog treatment, all but 1 patient presented HLA-DR staining. HLA-DR expression of these 32 patients was scored as mild (19 patients), medium (11 patients), or intense (2 patients). The differences were statistically significant both when the presence and the increased expression of HLA-DR were considered (P<0.001). When the 3 different groups were analyzed (latanoprost, bimatoprost, and travoprost) no statistically significant difference was found (P=0.27). CONCLUSIONS: The use of prostaglandin analogs eye drops provokes a subclinical inflammatory reaction, observed by HLA-DR expression, even after a short period of treatment, independently of the class of the prostaglandin analogs used.

[Circadian rhythm variations of intraocular pressure and therapeutic decisions: interpretation of clinical trial results based on a statistical model]. / Variations nycthémérales de la pression intraoculaire et décisions thérapeutiques: Interprétation des résultats d'essais cliniques à partir d'un modèle statistique.

Therapeutic decisions (treatment initiation, continuation, change, combination, etc.) based on intraocular pressure (IOP) monitoring require knowledge of both circadian IOP fluctuations and the pharmacological circadian rhythm of the active ingredients. A simple model was applied to data from two clinical trials to estimate the consequences of circadian IOP fluctuations on (1) ocular hypertension diagnosis, (2) therapeutic adjustments, and (3) the daily cumulative effect of marginally low therapeutic differences. A grid for clinical interpretation of the average IOP differences is presented. The probability of an IOP that exceeds the target value for the diagnosis or therapy varied to a large extent throughout the day. IOP was higher in the morning than in the evening. The IOP variance (measured by standard deviation) was an important factor in decision-making, regardless of the IOP value itself. Regular IOP monitoring over the entire day allowed minimization of the time spent above a target value. IOP differences that seemed low when expressed in average values in therapeutic trials could have clinically significant consequences in the practitioner's decisions. The data presented suggest that ocular hypertension diagnosis and therapeutic decisions should be made early in the morning, at least for most patients. In any case, the time of the measurement should be considered in the therapeutic approach.

Effects of travoprost 0.004% ophthalmic solution, six weeks after its laminated packaging had been removed, in primary open-angle glaucoma: a randomized, controlled, investigator-blinded study.

BACKGROUND: Primary open-angle glaucoma (POAG) is a chronic and progressive optic nerve and retinal nerve fiber layer neuropathy, with characteristic visual field damage. The intraocular pressure (IOP) is typically higher than the level considered statistically normal. Although there is no known cure, appropriate reduction of IOP with hypotensive drugs (eg, the topical prostaglandin analogue travoprost) delays the progression of POAG. Chemical-stability studies of travoprost performed by the manufacturer suggest that the stability of travoprost is maintained beyond the expiration date, which is 6 weeks after the laminated packaging has been opened. OBJECTIVE: The goal of this study was to assess the efficacy and tolerability of travoprost 0.004% ophthalmic solution, 6 to 12 weeks after its expiration date, in patients with POAG. METHODS: This randomized, controlled, investigator-blinded study was conducted at 2 centers in Brazil: the Ophthalmology Department, Federal University of Goiás, Goiânia, and the Ophthalmology Department, Santa Casa de Misericordia Hospital in São José do Rio Preto, Sao Paulo. Patients with POAG (in 1 or both eyes) were randomly assigned to receive travoprost, either from a bottle from which the laminated packaging had been removed and that had been stored at room light and temperature for 6 weeks (ie, after the expiration date; opened group), or from a bottle that had been sealed until first use by the patient (control group). Drug was to be administered, 1 drop in the lower conjunctival sac (in the affected eye[s]), QD between 7 pm and 9 pm, for 6 weeks. IOP was measured at study weeks 0 (baseline), 4, and 6. The 2 treatment groups were compared with regard to hypotensor effect and incidence of adverse events (AEs). RESULTS: : Thirty-one patients completed the study (55 eyes; 28 right and 27 left eyes; 35 eyes of women, 20 eyes of men). The mean (SD) ages of the opened and control groups were 61.8 (13.5) and 62.8 (14.1) years, respectively. Twenty-four patients were included in both treatment groups (ie, 1 eye per group). The baseline IOP was similar between the 2 treatment groups. There was a significant reduction in IOP in both groups at 4 and 6 weeks (both, P < 0.001 vs baseline). However, no significant differences in IOP were found between the 2 treatment groups at any time during the study. Conjunctive hyperemia and a burning sensation in the eye immediately after application were the only AEs reported; the incidence of these was similar between the 2 treatment groups. CONCLUSIONS: In this study of patients with POAG, IOPs and AEs were similar in eyes receiving 6 weeks of treatment with travoprost 0.004% ophthalmic solution, either from bottles from which the laminated packaging had been opened and that had been stored at room light and temperature for 6 weeks (ie, after the expiration date), or from bottles that had been sealed until first use by the patient. These results suggest that travoprost remains effective for at least 12 weeks after the laminated packaging has been opened.

Ocular hypotensive FP prostaglandin (PG) analogs: PG receptor subtype binding affinities and selectivities, and agonist potencies at FP and other PG receptors in cultured cells.

Natural prostaglandins (PGs) such as PGD2, PGE2, PGF2(2alpha), and PGI2 exhibited the highest affinity for their respective cognate receptors, but were the least selective agents when tested in receptor binding assays. Travoprost acid ([+]-fluprostenol) was the most FP-receptor-selective compound, exhibiting a high affinity (Ki = 35 +/- 5 nM) for the FP receptor, and minimal affinity for DP (Ki = 52,000 nM), EP1 (Ki = 9540 nM), EP3 (Ki = 3501 nM), EP4 (Ki = 41,000 nM), IP (Ki > 90,000 nM), and TP (Ki = 121,000 nM) receptors. Travoprost acid was the most potent PG analog tested in FP receptor functional phosphoinositide turnover assays in the following cell types: human ciliary muscle (EC50 = 1.4 nM), human trabecular meshwork (EC50 = 3.6 nM), and mouse fibroblasts and rat aortic smooth muscle cells (EC50 = 2.6 nM). Although latanoprost acid exhibited a relatively high affinity for the FP receptor (Ki = 98 nM), it had significant functional activity at FP (EC50 = 32-124 nM) and EP1 (EC50 = 119 nM) receptors. Bimatoprost acid was less selective, exhibiting a relatively high affinity for the FP (Ki = 83 nM), EP1 (Ki = 95 nM), and EP3 (Ki = 387 nM) receptors. Bimatoprost acid exhibited functional activity at the EP1 (EC50 = 2.7 nM) and FP (EC50 = 2.8-3.8 nM in most cells) receptors. Bimatoprost (nonhydrolyzed amide) also behaved as an FP agonist at the cloned human FP receptor (EC50 = 681 nM), in h-TM (EC50 = 3245 nM) and other cell types. Unoprostone and S-1033 bound with low affinity (Ki = 5.9 microM to > 22 microM) to the FP receptor, were not selective, but activated the FP receptor. In conclusion, travoprost acid has the highest affinity, the highest FP-receptor-selectivity, and the highest potency at the FP receptor as compared to the other ocular hypotensive PG analogs known so far, including free acids of latanoprost, bimatoprost, and unoprostone isopropyl ester.

Preclinical efficacy of travoprost, a potent and selective FP prostaglandin receptor agonist.

Travoprost is the isopropyl ester prodrug of a high affinity, selective FP prostaglandin full receptor agonist. In contrast to travoprost acid's high affinity and efficacy at the FP receptor, there is only sub-micromolar affinity for the DP, EP1, EP3, EP4, IP, and TP receptors. Travoprost produced a lower incidence of ocular irritation than PGF20 isopropyl ester at a dose of 1 microg in the New Zealand albino (NZA) rabbit. Topical ocular application of travoprost produced a marked miotic effect in cats following doses of 0.01, 0.03 and 0.1 microg. In the ocular hypertensive monkey, b.i.d. application of 0.1 and 0.3 microg of travoprost afforded peak reduction in intraocular pressure (IOP) of 22.7% and 28.6%, respectively. Topical application of travoprost was well tolerated in rabbits, cats and monkeys, causing no ocular irritation or discomfort at doses up to 1 microg. Travoprost is a promising ocular hypotensive prostaglandin FP derivative that has the ocular hypotensive efficacy of PGF2alpha isopropyl ester but with less severe ocular side effects.