Ocular Hypotensive Effect Research Articles

Ocular Hypotensive Effect of ONO-9054, an EP3/FP Receptor Agonist: Results of a Randomized, Placebo-controlled, Dose Escalation Study

To assess pharmacodynamic and safety profiles of ONO-9054 following single and multiple day dosing in subjects with ocular hypertension or open-angle glaucoma. This was a phase I, single-center, randomized, double-masked, placebo-controlled dose-escalation study. Nine subjects were randomized to each of ONO-9054 3, 10, 20, 30 μg/mL and 12 to placebo. Subjects received a single drop to each eye at 07:00±30 minutes (single dose). Following a 4-day no-treatment period, subjects were dosed once daily for 14 consecutive days (multiple day dosing). Intraocular pressure (IOP) was measured regularly and compared with baseline measurements. Ocular examinations assessed safety and tolerability. Mean IOP decreased dose dependently. Following single dosing, IOP decreased from 22.9±4.0 to 15.9±2.3 mm Hg (ONO-9054, 30 μg/mL) at peak effect 9 hours postdose; the reduction in placebo-treated subjects was from 22.3±2.4 to 21.5±3.3 mm Hg. Following multiple day dosing, the greatest reduction in IOP occurred 1 hour postdose on day 18, from 23.3±0.6 to 15.1±2.4 mm Hg (ONO-9054, 10 μg/mL); the smallest reduction at this time was from 23.9±0.8 to 18.6±2.0 mm Hg (ONO-9054, 3 μg/mL). Pressures remained reduced on day 19, 25 hours after the last dose, when the lowest measurement was 15.8±2.1 mm Hg (ONO-9054, 10 μg/mL). Anterior uveitis and vitreous detachment were each reported in 2 subjects and considered moderate by the Investigator. Ocular hyperemia and tolerability symptoms were generally mild and transient. ONO-9054 was well-tolerated and elicited dose-dependent reductions in IOP, which were sustained for at least 24 hours following 2 weeks of consecutive daily dosing.

Ocular hypotensive effect of fixed-combination brinzolamide/brimonidine adjunctive to a prostaglandin analog: a randomized clinical trial.

PurposeTo determine whether intraocular pressure (IOP) lowering with fixed-combination brinzolamide/brimonidine (BBFC) adjunctive to a prostaglandin analog (PGA) was superior to that of vehicle+PGA in patients with open-angle glaucoma or ocular hypertension who were inadequately controlled with PGA monotherapyMethodsThis 6-week, multicenter, randomized, double-masked, parallel-group trial was conducted at 30 clinical sites in the United States between October 2013 and May 2014. Eligible patients were adults with open-angle glaucoma or ocular hypertension and with mean IOP ≥21 and <32 mm Hg, whereas receiving an open-label PGA (latanoprost, bimatoprost, or travoprost). Patients instilled a PGA once-daily in a run-in phase before randomization to masked BBFC or vehicle adjunctive treatment. Masked treatments were instilled 3 times daily for 6 weeks, and patients continued once-daily use of their PGA. The primary efficacy end point was the between-group difference in mean diurnal IOP (average of 0800, 1000, 1500, and 1700 hours time points) at week 6.ResultsAt week 6, mean diurnal IOP with BBFC+PGA was lower than with vehicle+PGA (17.1±0.4 mm Hg vs 20.5±0.4 mm Hg; between-group difference, −3.4±0.5 mm Hg; P<0.0001; 95% confidence interval, −4.5 to −2.4 mm Hg). BBFC+PGA reduced mean diurnal IOP by 5.7 mm Hg (25%) from the baseline IOP achieved with PGA monotherapy.ConclusionsTherapy with BBFC produced an additive IOP-lowering effect compared with a PGA alone or in conjunction with vehicle. BBFC may provide an effective treatment option for patients receiving PGA monotherapy who require additional IOP reduction.

Pediatric Glaucoma: Pharmacotherapeutic Options.

Childhood glaucoma is a major therapeutic challenge for pediatric ophthalmologists and glaucoma specialists worldwide. Management depends on the etiology and age at presentation. A variety of drugs are available for the control of intraocular pressure in children; however, none of these drugs have been licensed by the regulatory agencies for use in children. Furthermore, evidence gained from randomized controlled trials in the pediatric population is sparse, and little is known regarding the use of newer anti-glaucoma preparations. This evidence-based review aims to discuss the available pharmacotherapeutic options for glaucoma in children. Topical adrenoceptor blockers, topical and systemic carbonic anhydrase inhibitors, prostaglandin (PG) analogs, adrenoceptor agonists, parasympathomimetics, and combined preparations are available for use in children, but usually as an off-label indication. Therefore, it is important to recognize that serious side effects have been reported, even with topical drops, and measures to reduce systemic absorption should be taken. Most drugs have been shown to have comparable ocular hypotensive effects, with the lowest occurrence of systemic side effects with PG analogs. Whereas a newly introduced prostaglandin analog, tafluprost, and some other preservative-free preparations have shown promising results in adult glaucoma patients, no pediatric reports are available as yet. Future studies may describe their role in treating pediatric glaucoma. This review also shares some suggested treatment pathways for primary congenital glaucoma (PCG), juvenile open angle glaucoma (JOAG), developmental glaucoma, aphakic/pseudophakic glaucoma, and uveitic glaucoma.

Neuroprotective Effect of Ocular Hypotensive Drugs: Latanoprost/Timolol in Combination Are More Effective than Each as Monotherapy in RGC-5.

The combination of timolol and latanoprost, which are ocular hypotensive agents, has a greater ocular hypotensive effect than each as monotherapy. However, the protective effect of the combination is not well understood. In the present study, we investigated whether latanoprost/timolol in combination has an additive or synergistic cytoprotective effect on neuro retinal cells (RGC-5). To investigate the protective effects of timolol/latanoprost in combination, cultured RGC-5 were treated with various concentrations of these two agents, singly or together, after which the cells were exposed to oxidative stress, serum deprivation, or endoplasmic reticulum (ER) stress in vitro. Cells were also treated with an Akt inhibitor, LY294002, to examine the mechanism of the protective effect. Latanoprost, timolol, and the two in combination reduced cell death induced by oxidative stress, serum deprivation, or ER stress. The latanoprost/timolol combination reduced cell death to a greater extent than monotherapy with latanoprost or timolol on serum deprivation only, and LY294002 inhibited the protective effect of their combination. These findings suggest that timolol/latanoprost in combination have a protective effect against serum deprivation only by activation of Akt signaling. Furthermore, this combination has not only an ocular hypotensive effect but also a neuroprotective effect.

Ocular hypotensive effect of fixed-combination brinzolamide/brimonidine adjunctive to a prostaglandin analog: a randomized clinical trial

Ocular hypotensive effect of fixed-combination brinzolamide/brimonidine adjunctive to a prostaglandin analog: a randomized clinical trial

Correction: Ocular Hypotensive Effects of the ATP-Sensitive Potassium Channel Opener Cromakalim in Human and Murine Experimental Model Systems

Elevated intraocular pressure (IOP) is the most prevalent and only treatable risk factor for glaucoma, a leading cause of irreversible blindness worldwide. Unfortunately, all current therapeutics used to treat elevated IOP and glaucoma have significant and sometimes irreversible side effects necessitating the development of novel compounds. We evaluated the IOP lowering ability of the broad spectrum KATP channel opener cromakalim. Cultured human anterior segments when treated with 2 μM cromakalim showed a decrease in pressure (19.33 ± 2.78 mmHg at 0 hours to 13.22 ± 2.64 mmHg at 24 hours; p<0.001) when compared to vehicle treated controls (15.89 ± 5.33 mmHg at 0 h to 15.56 ± 4.88 mmHg at 24 hours; p = 0.89). In wild-type C57BL/6 mice, cromakalim reduced IOP by 18.75 ± 2.22% compared to vehicle treated contralateral eyes (17.01 ± 0.32 mmHg at 0 hours to 13.82 ± 0.37 mmHg at 24 hours; n = 10, p = 0.002). Cromakalim demonstrated an additive effect when used in conjunction with latanoprost free acid, a common ocular hypotensive drug prescribed to patients with elevated IOP. To examine KATP channel subunit specificity, Kir6.2(-/-) mice were treated with cromakalim, but unlike wild-type animals, no change in IOP was noted. Histologic analysis of treated and control eyes in cultured human anterior segments and in mice showed similar cell numbers and extracellular matrix integrity within the trabecular meshwork, with no disruptions in the inner and outer walls of Schlemm’s canal. Together, these studies suggest that cromakalim is a potent ocular hypotensive agent that lowers IOP via activation of Kir6.2 containing KATP channels, its effect is additive when used in combination with the commonly used glaucoma drug latanoprost, and is not toxic to cells and tissues of the aqueous humor outflow pathway, making it a candidate for future therapeutic development.

Ocular Hypotensive Effects of the ATP-Sensitive Potassium Channel Opener Cromakalim in Human and Murine Experimental Model Systems.

Elevated intraocular pressure (IOP) is the most prevalent and only treatable risk factor for glaucoma, a leading cause of irreversible blindness worldwide. Unfortunately, all current therapeutics used to treat elevated IOP and glaucoma have significant and sometimes irreversible side effects necessitating the development of novel compounds. We evaluated the IOP lowering ability of the broad spectrum KATP channel opener cromakalim. Cultured human anterior segments when treated with 2 μM cromakalim showed a decrease in pressure (19.33 ± 2.78 mmHg at 0 hours to 13.22 ± 2.64 mmHg at 24 hours; p<0.001) when compared to vehicle treated controls (15.89 ± 5.33 mmHg at 0 h to 15.56 ± 4.88 mmHg at 24 hours; p = 0.89). In wild-type C57BL/6 mice, cromakalim reduced IOP by 18.75 ± 2.22% compared to vehicle treated contralateral eyes (17.01 ± 0.32 mmHg at 0 hours to 13.82 ± 0.37 mmHg at 24 hours; n = 10, p = 0.002). Cromakalim demonstrated an additive effect when used in conjunction with latanoprost free acid, a common ocular hypotensive drug prescribed to patients with elevated IOP. To examine KATP channel subunit specificity, Kir6.2(-/-) mice were treated with cromakalim, but unlike wild-type animals, no change in IOP was noted. Histologic analysis of treated and control eyes in cultured human anterior segments and in mice showed similar cell numbers and extracellular matrix integrity within the trabecular meshwork, with no disruptions in the inner and outer walls of Schlemm’s canal. Together, these studies suggest that cromakalim is a potent ocular hypotensive agent that lowers IOP via activation of Kir6.2 containing KATP channels, its effect is additive when used in combination with the commonly used glaucoma drug latanoprost, and is not toxic to cells and tissues of the aqueous humor outflow pathway, making it a candidate for future therapeutic development.

Anti-glaucoma potential of Heliotropium indicum Linn in experimentally-induced glaucoma.

BackgroundHeliotropium indicum is used as a traditional remedy for hypertension in Ghana. The aim of the study was to evaluate the anti-glaucoma potential of an aqueous whole plant extract of H. indicum to manage experimentally-induced glaucoma.MethodsThe percentage change in intraocular pressure (IOP), after inducing acute glaucoma (15 mLkg−1 of 5 % dextrose, i.v.), in New Zealand White rabbits pretreated with Heliotropium indicum aqueous extract (HIE) (30–300 mgkg−1), acetazolamide (5 mgkg−1), and normal saline (10 mLkg−1) per os were measured. IOPs were also monitored in chronic glaucoma in rabbits (induced by 1 % prednisolone acetate drops, 12 hourly for 21 days) after treatments with the same doses of HIE, acetazolamide, and normal saline for 2 weeks. The anti-oxidant property of the extract was assessed by assaying for glutathione levels in the aqueous humour. Glutamate concentration in the vitreous humour was also determined using ELISA technique. Histopathological assessment of the ciliary bodies was made.ResultsThe extract significantly reduced intraocular pressure (p ≤ 0.05–0.001) in acute and chronic glaucoma, preserved glutathione levels and glutamate concentration (p ≤ 0.01–0.001). Histological assessment of the ciliary body showed a decrease in inflammatory infiltration in the extract and acetazolamide-treated group compared with the normal saline-treated group.ConclusionThe aqueous whole plant extract of Heliotropium indicum has ocular hypotensive, anti-oxidant and possible neuro-protective effects, which therefore underscore its plausible utility as an anti-glaucoma drug with further investigation.

Comparison of two- and three-times-daily topical ophthalmic application of 0.005% latanoprost solution in clinically normal dogs.

To determine whether 2- or 3-times-daily application of topical ophthalmic 0.005% latanoprost solution is more effective at lowering intraocular pressure (IOP) in clinically normal dogs. 9 clinically normal dogs. For each dog, I drop of latanoprost 0.005% solution was applied to 1 eye every 8 or 12 hours each day for 5 days; the contralateral eye received topical ophthalmic treatment with 1 drop of saline (0.9% NaCl) solution at the times of latanoprost application. Ocular examinations of both eyes were performed every 6 hours starting 48 hours prior to and ending 42 hours after the treatment period. Following a 5-week washout interval, the procedures were repeated but the previously latanoprost-treated eye of each dog received latanoprost application at the alternate frequency. Mean ± SD IOP reduction in the latanoprost-treated eyes was 31 ± 6.9% with 2-times-daily application and 33 ± 8.2% with 3-times-daily application. A 2-way repeated-measures ANOVA revealed significant differences in IOP with contributions by treatment (2 or 3 times daily), time of day (diurnal variation), and individual dog. The maximum mean daily IOP reduction in latanoprost-treated eyes was detected on day 3 of latanoprost treatment in each group. Eyes treated 3 times daily had significantly smaller pupil diameter and greater conjunctival hyperemia than eyes treated 2 times daily. The clinical importance of the ocular hypotensive effects of 3-times-daily topical ophthalmic application of 0.005% latanoprost solution in dogs with glaucoma warrants investigation.

Evaluation of cationic nanosystems with melatonin using an eye-related bioavailability prediction model

In this study, two types of nanosystems, namely lecithin/chitosan nanoparticles and Pluronic® F127/chitosan micelles, have been prepared and evaluated for their potential for the ocular delivery of melatonin, which is known to exert an ocular hypotensive effect. The melatonin content, particle size, zeta potential and in vitro drug release properties were studied as a function of the presence of chitosan in the nanosystem. Lecithin/chitosan nanoparticles were evaluated in terms of the mucoadhesive properties by a newly established method based on HCE-T cells, also used in in vitro biocompatibility and permeability studies.Lecithin/chitosan nanoparticles were significantly larger than the corresponding F127/chitosan micelles (mean diameter of 241.8 vs. 20.7nm, respectively) and characterised by a higher surface charge (22.7 vs. 4.3mV, respectively). The HCE-T cell viability assay did not show significant toxic effects of nanosystems investigated at the (relevant) chitosan concentration tested. The permeability study results confirmed the permeation enhancing effect of F127, which was hindered in the presence of chitosan. Lecithin/chitosan nanoparticles were characterised by prominent mucoadhesive properties and prolonged melatonin release, which was shown to control melatonin permeation across an in vitro corneal epithelial model. Such properties demonstrate the potential for nanoparticles to provide an extended pre-corneal residence time of melatonin, ensuring higher eye-related bioavailability and extended intraocular pressure reduction compared to melatonin in both aqueous and micelle solutions.

Safety and efficacy of travoprost solution for the treatment of elevated intraocular pressure

Travoprost is a prostaglandin analogue widely used for reducing intraocular pressure (IOP) in patients affected with glaucoma and ocular hypertension. It exerts its ocular hypotensive effect through the prostaglandin FP receptors, located in the ciliary muscle and the trabecular meshwork. Several studies have shown that topical administration of travoprost induces a mean IOP reduction ranging from 25% to 32%, and sustained throughout the 24-hour cycle. When compared with timolol, travoprost is more effective at reducing IOP, while generally no difference has been found in the head-to-head comparison with other prostaglandin analogues. The fixed combination of travoprost and timolol has demonstrated a hypotensive efficacy comparable to the concomitant administration of the two drugs. Recently, a new preservative-free formulation of travoprost 0.004% has been marketed for reducing tolerability-related problems in subjects affected with ocular surface disease. Low rates of topical and systemic adverse reactions, strong ocular hypotensive efficacy, and once-a-day dosing make travoprost a first-line treatment for patients affected with elevated IOP.

Evaluation of ocular hypotensive effects of some drugs used in treatment of open angle glaucoma, at Alsaym Ophthalmic Hospital, Wad Medani, Sudan

Introduction: Glaucoma is a neurodegenerative disease. It is presented by a triad of elevated intraocular pressure (IOP), progressive optic nerve damage, and constriction of the peripheral visual field. Objectives: The aim of this study is to assess the ocular hypotensive effects of some drugs used in treatment of open angle glaucoma (OAG) at Alsaym Ophthalmic Hospital, Wad Medani, Sudan. Methodology: A cross-sectional hospital-based study was conducted at specialized ophthalmological health setting. Patients (n = 200) diagnosed with OAG and treated with different anti-glaucoma drugs were selected randomly to participate in this study. The ocular hypotensive effects of anti-glaucoma drugs were evaluated monthly for 4 successive months, by measuring the diurnal IOP for each patient, using tonometer. The obtained data were collected in especial data collection form and analyzed by IBM SPSS Inc. (IBM SPSS Statistics) Software;Group's Business Analytics Portfolio. Results: Monotherapy of timolol (eye drops 0.5% and 0.1% eye gel), betaxolol 0.5% eye drops produced significant reductions in the total mean of IOP, ranged between 4.4 and 6.1 mmHg, while travoprost 0.004% eye drops showed a remarkable reduction of 7.3 mmHg. Combinations of travoprost with timolol and and/or dorzolamide 2% resulted in significant IOP lowering effects, ranged from 8.9 to 12.7 mmHg. Mono or combined therapy with travoprost was found to be superior to other anti-glaucoma monotherapy. Conclusion: The obtained results showed that travoprost produced clinical significant and superior ocular hypotensive effects when used alone or in combination with timolol and/or dorzolamide. It is thus recommended to use prostaglandin analogues in treatment of OAG because they are the most effective agents in reducing the mean diurnal IOP.

Cationic solid lipid nanoparticles enhance ocular hypotensive effect of melatonin in rabbit

The study was aimed at evaluating whether the ocular hypotensive effect of melatonin (MEL) was enhanced by its encapsulation in cationic solid lipid nanoparticles (cSLN), as well as at determining the tolerability of these formulations on the ocular surface. MEL was loaded in cSLN that had already been shown to be suitable for ophthalmic use. The formulations were prepared using Softisan® 100 as the main lipid matrix, with the presence of either stearic (SA) or palmitic acid (PA) as lipid modifiers. A fixed positive charge was provided by the addition of a cationic lipid (didecyldimethylammonium bromide). The ocular hypotensive effect was evaluated by measuring the intraocular pressure (IOP) during 24h in albino rabbits. MEL elicited a significant (p<0.01) IOP reduction in rabbit eye. All the formulations tested in vivo demonstrated a good tolerability. The nanocarrier containing SA was the most effective in terms of IOP reduction (maximum IOP reduction: −7mmHg), and its effect lasted approximately 24h.The experimental data indicate that the new formulations based on cSLN loaded with MEL represent a potent anti-glaucoma treatment with a safe profile, warranting further clinical evaluation of the proposed nanotechnological strategy.

The ocular hypotensive effect of saffron extract in primary open angle glaucoma: a pilot study.

BackgroundThe progressive nature of glaucoma and its growing incidence make its therapy an important target for research. The role of oxidative damage in the pathogenesis of glaucoma makes antioxidants such as saffron extract an attractive target for potential clinical use. Herein, we evaluate the effect of aqueous saffron extract on intraocular pressure (IOP) in eyes with primary open-angle glaucoma (POAG).MethodsThirty-four eyes of 34 clinically stable POAG patients receiving treatment with timolol and dorzolamide eye drops were enrolled in this prospective, comparative, randomized interventional pilot study. Eligible subjects were randomized to receive 30 mg/day aqueous saffron extract orally (17 subjects, 17 eyes) or placebo (17 subjects, 17 eyes) for one month as an adjunct to timolol and dorzolamide. Following treatment, both study groups entered a one-month wash-out period. The main outcome measure was IOP during treatment and after the wash-out period.ResultsMean baseline IOP was 12.9 ± 3.7 versus 14.0 ± 2.5 mmHg in the saffron and control groups, respectively (p = 0.31). After three weeks of treatment, IOP was significantly decreased to 10.9 ± 3.3 mmHg in the saffron group as compared to 13.5 ± 2.3 mmHg in the control group (p = 0.013). At four weeks, IOP was still significantly lower in the saffron group (10.6 ± 3.0 versus 13.8 ± 2.2 mmHg, p = 0.001). At the end of the wash-out period, IOP was 12.9 ± 3.0 in the saffron group versus 14.2 ± 2.0 mmHg in the control group (p = 0.175). None of the patients experienced side effects during the study and wash-out period.ConclusionsOral aqueous saffron extract seems to exert an ocular hypotensive effect in primary open-angle glaucoma. This effect became evident after three weeks of therapy.The current study was registered at the International Clinical Trials Registry Platform (ICTRP) as IRCT201201278832N1.

Chitosan nanoparticles amplify the ocular hypotensive effect of cateolol in rabbits

PurposeTo assess the potential of chitosan (CS) nanoparticles for ocular drug delivery by investigating their intraocular retention by γ-scintigraphy and intraocular pressure reduction. MethodsCarteolol (CRT) loaded CS-NPs were prepared by ionotropic gelation method. A four-factor three-level Box–Behnken design was employed to investigate the influence of independent variables on particle size, loading capacity and entrapment efficiency. Characterization was done for particle size, encapsulation efficiency, loading capacity and in vitro drug release and transcorneal permeation, histopathology and confocal microscopy, in vitro ocular tolerance. Intraocular retention was assessed by γ-scintigraphy, and intraocular pressure was measured by tonometer betamethasone induced glaucoma rabbits. Results and discussionThe optimized nanoparticles showed a particle size of 243nm (PDI – 0.304±0.04) and drug loading 49.21±2.73% with entrapment efficiency of 69.57±3.54%. In vitro release studies showed a sustained release for 24h as compared to drug solution. Ex vivo studies showed good permeation with non-significant changes in cornea anatomy indicating its safe nature. γ-Scintigraphy study showed good spread and retention (<0.05) in precorneal area as compared to the aqueous CRT solution and prolonged reduction in intraocular pressure (P<0.001). ConclusionThese results indicate that CS nanoparticles are promising vehicles of CRT for ocular drug delivery.

Not only pregnancy but also the number of fetuses in the uterus affects intraocular pressure

Aim:To investigate whether, intraocular pressure (IOP) is affected when there is a second fetus in the uterus during pregnancy.Materials and Methods:Eighty eyes of 40 twin pregnancies (TwPs), 80 eyes of 40 singleton pregnancies (SiPs) and 80 eyes of 40 non-pregnant females (NoPs) were included in the study.Statistical Analysis:Repeated measurements analysis of variance with two factors, one-way analysis of variance (ANOVA) and theTukey's multiple comparison test were used.Results:The mean IOP (MIOP) values in TwPs were 14.29 ± 1.28, 11.48 ± 1.20, and 9.81 ± 1.36 mmHg and the MIOP values in SiPs were 14.42 ± 0.95, 13.12 ± 0.75, and 10.97 ± 0.89 mmHg in subsequent trimesters. The MIOP values in NoPs were 14.77 ± 1.18, 14.92 ± 1.33, and 15.08 ± 0.89 mmHg in subsequent 3-month measurements. The results show that the MIOP values for the TwPs group were significantly lower than the SiPs in all trimesters.Conclusions:During pregnancy, the number of fetuses in the uterus is an indirectly important factor that influences the decrease in IOP. We hypothesize that the increased ocular hypotensive effect of TwPs is most likely related to the presence of higher levels of hormones, particularly estrogen, progesterone and relaxin compared with SiPs.

Efficacy and Safety of Trabeculectomy vs Nonpenetrating Surgical Procedures

To date, only a few studies have directly compared nonpenetrating surgery (NPS) and trabeculectomy (TE). Therefore, there is no strong evidence as to which surgical technique leads to the best results in terms of ocular hypotensive effect and safety. To compare the hypotensive effect and safety of NPS and TE in terms of intraocular pressure (IOP) reduction and incidence of complications. The MEDLINE and EMBASE databases were searched for studies potentially eligible in any language published up to March 31, 2013. Systematic review and meta-analysis of comparative studies of 2 or more surgical techniques (1 of which had to be TE), including patients with open-angle glaucoma. The considered interventions were TE, deep sclerectomy (DS), viscocanalostomy, and canaloplasty. The primary outcome was the mean between-group difference in the reduction in diurnal IOP from baseline to the 6- or 12-month follow-up evaluation. We also considered the incidence of complications, expressed as relative risk. Eighteen articles, accounting for 20 comparisons, were selected for data extraction and analysis. Analysis of the 6-month follow-up data showed that the pooled estimate of the mean between-group difference was -2.15 mm Hg (95% CI, -2.85 to -1.44) in favor of TE. There was no difference between the NPS subgroups. In the subgroup antimetabolite analysis, the addition of mitomycin C to TE and DS decreased the difference in the reduction in IOP (TE and DS without mitomycin C: -2.65 mm Hg [95% CI, -3.90 to -1.39]; TE and DS with mitomycin C: -0.83 mm Hg [95% CI, -2.40 to 0.74]). In the subgroup analysis by implant addition, no significant difference induced by DS with or without drainage devices was detected (test for subgroup differences: χ(2)(1) = 0.24; P = .62). The absolute risk of hypotony, choroidal effusion, cataract, and flat or shallow anterior chamber was higher in the TE group than in the NPS group. Trabeculectomy seems to be the most effective surgical procedure for reducing IOP in patients with open-angle glaucoma. However, as expected, it was associated with a higher incidence of complications when compared with NPS.

Trabecular Meshwork Bradykinin Receptors: mRNA Levels, Immunohistochemical Visualization, Signaling Processes Pharmacology, and Linkage to IOP Reduction

To localize mRNA and protein of bradykinin (BK) receptors, BK precursor polypeptide (kininogen) mRNA, and to study functional biochemical pharmacology of the signal transduction processes mediated by B2-receptors in isolated human trabecular meshwork (h-TM) cells. Intraocular pressure (IOP) lowering effects of 2 kinins were also investigated. Previously documented procedures were utilized throughout these studies. Kinninogen mRNA was most abundant in TM, ciliary body (CB), and optic nerve head and appeared elevated in glaucomatous h-TM tissue. High levels of B2-receptor mRNA were found in the sclera, iris, TM, and CB. B2-receptor subtype protein was localized in cells of the monkey and h-TM, and the treatment of isolated h-TM cells with transforming growth factor-β2 (5 ng/mL) caused significant (P<0.04) downregulation of B2-receptor mRNA. In isolated primary h-TM cells, BK (EC50=0.8±0.2 nM; n=19) and Met-Lys-BK (EC50=6.5±1.5 nM) mobilized intracellular Ca(2+) and induced the release of prostaglandins (PGs) that was blocked by 2 B2-receptor antagonists [HOE-140; (S)-WIN-64338]. The cyclooxygenase inhibitor, bromfenac, abolished BK-induced PGs production. BK concentration dependently increased cell impedance, and it significantly (P<0.05) decreased h-TM cell volume in vitro. Intravitreal (ivt) administration of BK (50 μg), but not a B1-agonist (Sar-[D-Phe(9)]-Des-Arg(9)-BK; also at 50 μg), efficaciously lowered IOP (22.9% to 37% from baseline) of Dutch-Belted rabbits that naturally have high IOPs (27-28 mmHg). BK activates multiple signal transduction pathways in h-TM cells via B2-receptors that also mediate IOP reduction as observed in rabbits following ivt administration of BK. These ocular hypotensive effects of BK may be physiologically important and suggest a novel therapeutic potential of BK-related B2-agonists.

Hypotensive Effect of Latanoprost/Timolol Versus Travoprost/Timolol Fixed Combinations in NTG Patients: A Randomized, Multicenter, Crossover Clinical Trial

To compare the ocular hypotensive effect of travoprost plus timolol (TTFC) and latanoprost plus timolol fixed combinations (LTFC) in patients with normal-tension glaucoma (NTG). A two-sequence 12-week, multicenter, prospective, randomized, single-blinded, crossover clinical trial examined 59 NTG patients. If both eyes were eligible, only one eye (chosen at random) was used for analytical purposes. After a 12-week run-in period with dorzolamide plus timolol fixed combination (DTFC), patients were randomized into one of the two crossover sequences of treatment for 12 weeks with TTFC or LTFC and were subsequently crossed over to the alternative treatment for a further 12 weeks. The primary endpoint was reduction in IOP after 12 weeks of each treatment sequence. The effect of treatment on IOP was assessed using a linear mixed model. The mean baseline IOP was 14.8 ± 3.3 mm Hg (95% confidence interval [CI], 14.1-15.3 mm Hg) for treatment with DTFC. The TTFC treatment period showed consistently lower mean IOP compared with LTFC treatment period at all measurement time points. Mean reduction in IOP at 12 weeks was significantly greater in the TTFC group than in the LTFC group (-2.4 ± 2.3 mm Hg vs. -1.1 ± 2.3 mm Hg; P = 0.021). No interaction between the drug and treatment sequence was detected. The effects of intraocular lens implantation and measurement time were also not significant. The tolerability profiles of both treatments were similar. The additional reduction in IOP was greater with TTFC than with LTFC, and their tolerability profiles were similar. (http://www.umin.ac.jp/ctr/ number, UMIN 000005974.).

Melatonin and Its Analog 5-Methoxycarbonylamino-N-Acetyltryptamine Potentiate Adrenergic Receptor-Mediated Ocular Hypotensive Effects in Rabbits: Significance for Combination Therapy in Glaucoma

Melatonin is currently considered a promising drug for glaucoma treatment because of its ocular hypotensive and neuroprotective effects. We have investigated the effect of melatonin and its analog 5-methoxycarbonylamino-N-acetyltryptamine, 5-MCA-NAT, on β₂/α(2A)-adrenergic receptor mRNA as well as protein expression in cultured rabbit nonpigmented ciliary epithelial cells. Quantitative polymerase chain reaction and immunocytochemical assays revealed a significant β₂-adrenergic receptor downregulation as well as α(2A)-adrenergic receptor up-regulation of treated cells (P < 0.001, maximal significant effect). In addition, we have studied the effect of these drugs upon the ocular hypotensive action of a nonselective β-adrenergic receptor (timolol) and a selective α₂-adrenergic receptor agonist (brimonidine) in normotensive rabbits. Intraocular pressure (IOP) experiments showed that the administration of timolol in rabbits pretreated with melatonin or 5-MCA-NAT evoked an additional IOP reduction of 14.02% ± 5.8% or 16.75% ± 5.48% (P < 0.01) in comparison with rabbits treated with timolol alone for 24 hours. Concerning brimonidine hypotensive action, an additional IOP reduction of 29.26% ± 5.21% or 39.07% ± 5.81% (P < 0.001) was observed in rabbits pretreated with melatonin or 5-MCA-NAT when compared with animals treated with brimonidine alone for 24 hours. Additionally, a sustained potentiating effect of a single dose of 5-MCA-NAT was seen in rabbits treated with brimonidine once daily for up 4 days (extra IOP decrease of 15.57% ± 5.15%, P < 0.05, compared with brimonidine alone). These data confirm the indirect action of melatoninergic compounds on adrenergic receptors and their remarkable effect upon the ocular hypotensive action mainly of α₂-adrenergic receptor agonists but also of β-adrenergic antagonists.