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Background/aimsTo assess the comparative efficacy of latanoprostene bunod (LBN), a novel prostaglandin analogue (PGA), to other medications for open-angle glaucoma and ocular hypertension on lowering intraocular pressure (IOP).MethodsA systematic literature review adapted from the Li et al (Ophthalmology, 2016) study was conducted. Medline, Embase and PubMed were searched for randomised controlled trials published between 1 January 2014 and 19 March 2020. Studies had to report IOP reduction after 3 months for at least two different treatments among placebo, PGAs (bimatoprost 0.01%, bimatoprost 0.03%, latanoprost, LBN, tafluprost, unoprostone) or apraclonidine, betaxolol, brimonidine, brinzolamide, carteolol, dorzolamide, levobunolol, timolol, travoprost. A Bayesian network meta-analysis was performed to provide the relative effect in terms of mean difference (95% credible interval) of IOP reduction and ranking probabilities. Surface under the cumulative ranking curve (SUCRA) was generated.ResultsA total of 106 trials were included with data for 18 523 participants. LBN was significantly more effective than unoprostone (−3.45 (−4.77 to −2.12)). Although relative effect was not significative, compared with other PGAs, LBN numerically outperformed latanoprost (−0.70 (−1.83 to 0.43)) and tafluoprost (−0.41 (−1.87 to 1.07)), was similar to bimatoprost 0.01% (-0.02(−1.59 to 1.55)) and was slightly disadvantaged by bimatoprost 0.03% (−0.17 (−1.42 to 1.07)). LBN was significantly more efficient than the beta-blockers apraclonidine, betaxolol, brimonidine, brinzolamide, carteolol, dorzolamide and timolol. According to SUCRA, LBN was ranked second after bimatoprost 0.03%, followed by bimatoprost 0.01%.ConclusionLBN was significantly more effective than the PGA unoprostone and most of the beta-blockers. Compared with the most widely used PGAs, LBN numerically outperformed latanoprost and travoprost and was similar to bimatoprost 0.01%.

PurposeThis study aimed to review previous articles and evaluate the influence of topical non-steroidal anti-inflammatory drugs (NSAIDs) on intraocular pressure (IOP) in glaucoma patients who were treated with prostaglandin analogues (PGs).MethodThe presenting study was designed as a meta-analysis of previous research. Databases include PubMed, Web of science, Cochrane library, and Embase were searched with keywords of "intraocular pressure, prostaglandin analogues, NSAIDs, latanoprost, travoprost, bimatoprost, tafluprost, unoprostone, latanoprostene bunod, ketorolac, diclofenac, nepafenac, bromfenac, flurbiprofen". Inclusion criteria were: 1. Study population were glaucoma patients; 2. Comparison between PGs monotherapy and PGs in combination with topical NSAIDs; 3. Changes of IOP as final outcomes. Studies with non-randomized design, treatments combining other anti-glaucomatous drugs, or unavailable absolute IOP were excluded from the analysis. Estimated difference in IOP were calculated using STATA 14.0.ResultSeven studies were retrieved for this meta-analysis. Since there is a significant heterogeneity (I2 = 94%) in these studies, random-effect model was used to calculate pooled standardized mean differences (SMD). Our results showed a significantly favorable IOP lowering effect in glaucoma patients treated with combination of topical NSAIDs and PGEs (SMD: 1.3 and -0.03, 95% CI: 0.29 to 2.38 and -0.32 to 0.26, Z = 2.50 and 0.23, p = 0.013 and 0.820, respectively).ConclusionResults of our meta-analysis suggested that topical NSAIDs may enhance the IOP lowering effect of topical PGs in glaucoma patients.

This investigation was conducted to study the relationship between intracellular Ca(2+) and activation of large conductance Ca(2+)-activated K(+) (BK) currents by unoprostone, the first synthetic docosanoid. We used HEK293 cells stably transfected with two BK channel splice variants, one sensitive to unoprostone and the other insensitive. We examined the effects of unoprostone on channel activity in excised inside-out patches and cell-attached patches. The half-maximal stimulation of the sensitive BK channels by Ca(2+) was shifted from 3.4±0.017 nM to 0.81±.0058 nM in the presence of 10 nM unoprostone. There was no effect on insensitive channels even at unoprostone concentrations as high as 1000 nM. There was no effect of unoprostone on the voltage dependence of the BK channels. Changes in open probability and effects of Ca(2+) and unoprostone were best described by a synergistic binding model. These data would suggest that Ca(2+) and unoprostone were binding to sites close to one another on the channel protein and that unoprostone binding causes the affinity of the calcium binding site to increase. This idea is consistent with three dimensional models of the Ca(2+) binding site and a putative unoprostone binding domain. Our results have important implications for the clinical use of unoprostone to activate BK channels. Channel activation will be limited if intracellular Ca(2+) is not elevated.

Bimatoprost, latanoprost, and unoprostone are prostaglandin F(2α) analogs (PGAs) and are used to lower intraocular pressure. We investigated the free acid effects of these three prostaglandin analogs: bimatoprost, latanoprost, and unoprostone on human matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMP) in the trabecular meshwork (TM) cells. Immunoblot results show that all three PGAs generally increased MMPs-1,9 and TIMPs-4. Additionally, bimatoprost and latanoprost both increased MMP-3 and TIMP-2, while unoprostone had an indeterminate effect on both. Zymography results show that all three PGAs except unoprostone increased intermediate MMP-1 activity while bimatoprost and latanoprost increased MMP-9 activity. Together, these data suggest that the balance between MMPs and TIMPs correlate to the relative intraocular pressure lowering effectiveness observed in clinical studies of these PGAs.

Purpose We evaluate the ocular tissue distribution and retinal toxicity of unoprostone (UNO) during 12 months, after transscleral sustained-UNO administration using a drug delivery device in monkey eyes. Methods The device consisted of a reservoir, controlled-release cover, and a drug formulation of photopolymerized polyethylene glycol dimethacrylate. Six mg UNO was loaded into the device (length, 17 mm; width, 4.4 mm; height, 1 mm). The concentrations of M1, a primary metabolite of UNO, in the retina, choroid, vitreous, lens, aqueous humor, iris, ciliary body, and plasma were determined by liquid chromatography-tandem mass spectrometry at 3, 6, and 12 months after implantation. Retinal toxicity was evaluated by electroretinography (ERG), optical coherence tomography (OCT), and IOP at preimplantation, and at 6, 9, and 12 months after implantation. Focal ERGs were performed at 9 and 12 months after implantation. Results M1 was detected in the choroid and retina with maximum peaks of 243.2 and 8.41 ng/g at 6 months, respectively. M1 in the ciliary body and iris was detected with maximum peaks of 7.66 and 10.4 ng/g at 6 and 12 months, respectively. Less than 1 ng/mL or ng/g of M1 was detected in the aqueous humor, vitreous, and lens. No changes were observed in retinal function as assessed by ERG, IOP, or macula thickness and retinal histology by OCT examinations during the 12-month period. No differences in focal ERG amplitudes, especially in the macula, were observed. Conclusions The device provided intraocular sustained delivery of UNO for 12 months without producing severe retinal toxicity.

It has been suggested that unoprostone isopropyl (UNO) has potent neuroprotective activity in the retina. The effect of sustained transscleral UNO delivery to the posterior segment of the eye on photoreceptor degeneration was evaluated. UNO was loaded into a device made of poly(ethyleneglycol) dimethacrylate by polydimethylsiloxane mold-based UV-curing. The amount of UNO diffusing from these devices was measured using high-performance liquid chromatography. The polymeric devices that released UNO at 1.8 μg/day were implanted on the sclerae of S334ter rats at postnatal 21 days, and electroretinograms (ERGs) were compared with those of topical application and placebo devices. Retinal thickness was evaluated by histological examination. Western blots of specimens 4 weeks after implantation were performed. ERGs showed that the UNO-loaded device prevented the reduction of ERG amplitudes 2 and 4 weeks after implantation, compared with results using a placebo device or topical application. Histological examination showed that the UNO-loaded device prevented the reduction of retinal thickness, and Western blots of specimens indicated that the UNO-loaded device decreased expression of ERK1/2, phosphorylated ERK1/2, and caspase-3. A device that provided sustained UNO administration protected against retinal degeneration in rhodopsin mutant rats, and thus, may have translational potential as a sustainable method to administer drugs to treat retinitis pigmentosa. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1730-1737, 2016.

Daisuke Takemoto, Tomomi Higashide, Yoshiaki Saito, Shinji Ohkubo, Sachiko Udagawa, Hisashi Takeda, Kazuhisa Sugiyama Department of Ophthalmology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan Purpose: We conducted a prospective study in patients with normal-tension glaucoma (NTG) who received either isopropyl unoprostone or latanoprost. We compared the drugs in terms of their effects on intraocular pressure (IOP) and visual field loss progression over a 3-year period. Study design: Prospective, randomized controlled study. Methods: We enrolled 48 patients with newly diagnosed NTG at Kanazawa University Hospital. Eligible patients were randomly allocated (1:1) to receive either unoprostone or latanoprost ophthalmic solutions. The primary outcomes were IOP changes and visual field deterioration within 36 months. Visual field changes were analyzed: the cumulative survival rates were calculated in terms of mean deviation, pattern standard deviation, and total deviation of the upper or lower hemi-visual field, each visual field sector, and guided progression analysis. In addition, we evaluated the progression of glaucomatous optic disc changes using fundus photography and confocal scanning laser ophthalmoscopy. Results: The mean pretreatment IOP was 15.0±2.4 mmHg in the Unoprostone group and 15.2±1.9 mmHg in the Latanoprost group. The mean IOP during the treatment period was 13.7±2.3 mmHg in the Unoprostone group and 13.0±1.8 mmHg in the Latanoprost group. In both groups, the IOP decreased significantly (p

Transscleral drug delivery is becoming increasingly popular to manage posterior eye diseases. To evaluate the clinical application of a transscleral, sustained, unoprostone (UNO)-release device (URD) constructed of photopolymerized tri(ethyleneglycol) dimethacrylate and poly(ethyleneglycol) dimethacrylate, we evaluated physicochemical and biological properties of this device. The URD consists of a drug-impermeable reservoir and a semi-permeable cover. The in vitro release rate of UNO from the URD increased with increasing temperatures from 20 to 45 °C. Scanning electron microscopy and atomic-force microscopy showed that the border between the reservoir and drug formulation was sharply defined but that between the cover and drug was poorly determined, indicating that UNO could permeate only through the cover. For stability tests, the URDs were sterilized with ethylene oxide gas and stored at 40 °C/75% for 3 and 6 months and at 25 °C/60% for 3, 6, 9, 12, 18, and 24 months; UNO content and release rate at 37 °C were then evaluated. There was no significant decrease in either UNO content or release rate after the storage conditions. Cytotoxicity was evaluated by examining the colony formation of Chinese hamster fibroblast V79 cells in a media extract of the URD without UNO. This extract did not affect colony formation of V79 cells, indicating the cytocompatibility of the URD. In conclusion, the URD was physically stable for 24 months and is potentially useful for clinical application.

Controlled transscleral co-delivery of two drugs, edaravone (EDV) and unoprostone (UNO), using a platform that comprises a microfabricated reservoir, controlled-release cover, and drug formulations, which are made of photopolymerized poly(ethyleneglycol) dimethacrylates, shows synergistic retinal neuroprotection against light injury in rats when compared with single-drug-loaded devices. The device would offer a safer therapeutic method than intravitreal injections for retinal disease treatments.

Glaucoma is a progressive, neurodegenerative optic nerve disease that can cause significant visual morbidity and affects over 60 million people worldwide. The only known modifiable risk factor for glaucoma at this time is elevated intraocular pressure (IOP), which may be treated with medications, laser therapy, and/or incisional surgery. Topical ocular medications are commonly used as first-line therapy for glaucoma, although side effects may limit their use. Unoprostone is a novel 22-carbon ocular hypotensive agent that may be advantageous in treating some patients with open angle glaucoma or ocular hypertension. Unlike the 20-carbon prostanoids, such as latanoprost, that lower IOP primarily through an increase in uveoscleral outflow, unoprostone may lower IOP through increased aqueous outflow via the conventional trabecular meshwork pathway. Although not as efficacious as other prostanoids, unoprostone is effective for IOP reduction both as monotherapy and adjunctive therapy with timolol. Unoprostone has decreased affinity for the prostaglandin F2α receptor, which may explain its well tolerated ocular and systemic side effect profile compared with other prostanoids.

Optic nerve and retinal diseases such as glaucoma, age-related macular degeneration (AMD) and retinitis pigmentosa (RP) are significant public health concerns and have a momentous impact on patients' functional status and quality of life. These diseases are among the most common causes of visual impairment worldwide and account for billions of dollars in healthcare expenditures and lost productivity. The importance of adequate treatment of these conditions and the need for efficacious therapeutic drugs cannot be overstated. Unoprostone continues to be developed as a potential treatment for these debilitating diseases.This review provides background information on unoprostone isopropyl (unoprostone), a prostanoid and synthetic docosanoid approved for the treatment of open-angle glaucoma and ocular hypertension, and recapitulates safety and efficacy data as it relates to this indication. Additionally, this review describes potential new uses of unoprostone as therapy for dry AMD and RP. A literature search of peer-reviewed publications was performed utilizing PubMed. Searches were last updated on 10 September 2012.Current data indicate that unoprostone does significantly lower intraocular pressure (IOP) and has a favorable safety and tolerability profile. However, the IOP-lowering effects of unoprostone do not compare with other commercially available prostanoids and it has the disadvantage of a twice-daily rather than once-daily dosing regimen. Nonetheless, recent data suggest that unoprostone may improve neuronal survival and increase ocular blood flow, indicating that it may have some value as a therapy for glaucoma, RP and dry AMD. Further studies are needed to confirm whether unoprostone provides any clinically significant advantage over the other commercially available prostanoids.

The discovery of potent and efficacious intraocular pressure (IOP)-lowering FP-class prostaglandin (PG) analogs has revolutionized the treatment of ocular hypertension, a major risk factor for progression of the blinding disease glaucoma. Three isopropyl ester pro-drugs (i.e., latanoprost, travoprost and unoprostone) and one amide pro-drug (bimatoprost) of w-chain-modified analogs of PGF2α are approved for lowering IOP and treating glaucoma. It is believed that these pro-drugs are sufficiently lipophilic to readily penetrate the cornea/conjunctiva upon topical ocular dosing whereupon they are hydrolyzed with liberation of their respective free acid into the aqueous humor. The free acids of these PGs activate the FP receptors in the ciliary muscle (CM) and trabecular meshwork (TM) and cause the release of matrix metalloproteinases that digest the extracellular matrix. This remodeling within the CM and TM creates new and/or enlarges fluid flow pathways, both uveoscleral and conventional, for aqueous humor e...

The visual acuity decline in glaucoma is due to degeneration of retinal ganglion cells. We used cell panning with the antibody Thy 1.1 to isolate retinal ganglion cells (RGCs) from rat retina. Individual RGCs were extremely sensitive to glutamate, demonstrating sustained calcium influx responses to 100 nm glutamate. We tested unoprostone for its ability to elicit neuroprotection. This docosanoid decreases intraocular pressure in glaucoma patients and protects mixed retinal ganglion cell cultures from glutamate excitotoxicity and calcium influx. In the presence of retinal glia, RGCs responded to 100 and 500 nm glutamate with transient calcium influx, demonstrating glial buffering effects. Pure retinal glial cultures required on average at least 1 mm glutamate to trigger calcium influx, which was transient and oscillating. Unoprostone (10 μm) inhibited calcium influx stimulated by 5 mm glutamate in retinal glial cultures, while DMSO did not. Unoprostone at 1 μm also blocked neuronal calcium responses to 100 nm glutamate in mixed cultures, while DMSO did not. In RGCs isolated by panning, unoprostone blocked calcium responses to 100 nm glutamate in some cells, while DMSO blocked none. Unoprostone also protected RGCs from 20 μm glutamate-induced toxicity and nuclear damage. We hypothesize that while unoprostone may affect individual RGCs depending on a putative receptor, the presence of retinal glia also plays a key role in neuroprotection and unoprostone action. The use of the cellular model described here and whole retina preparations will be useful to understand the mechanisms of RGC survival. Acknowledgements: Support: Novartis Ophthalmics, Basel, Switzerland.

PURPOSE To determine the effect of central corneal thickness (CCT) on the efficacy of intraocular pressure (IOP)-reducing drugs in patients with ocular hypertension (OHT). METHODS This retrospective study analyzed research records of 115 OHT patients and 97 ocular normotensive (ONT) volunteers. CCT was measured by slit-lamp pachymetry and IOP by pneumatonometry. The OHT patients were divided into Thick (>540 microm, n=52) and Thin (

The effect of unoprostone isopropyl on the intracellular free Ca 2+ signaling ([Ca 2+ ] i ) in cultured porcine corneal endothelial cells was evaluated by using fura-2-AM as a Ca 2+ probe. In Ca 2+ -containing buffer and Ca 2+ -free buffer, unoprostone increased [Ca 2+ ] i concentration dependently from 28.2 to 0.282 μM, diluted from original concentration to 1/100, 1/1000 and 1/10,000. The response was inhibited on extracellular Ca 2+ removal. In Ca 2+ -free buffer, pretreatment of the cells with unoprostone inhibited the endoplasmic reticulum Ca 2+ pump inhibitor thapsigargin-induced [Ca 2+ ] i increase and the mitochondria uncoupler carbonylcyanide m -chlorophenylhydrazone (CCCP)-induced Ca 2+ release by 96 and 95%, respectively. Pretreatment of the cells with thapsigargin or CCCP also inhibited unoprostone-1-induced [Ca 2+ ] i rise by 84 and 57%, respectively. The intracellular calcium release caused by unoprostone was partially inhibited by phospholipase C inhibitor (U73122) and by phospholipase A 2 inhibitor aristolochic acid. After incubation of the cells with unoprostone in Ca 2+ -free buffer, the addition of 5 mM CaCl 2 increased Ca 2+ influx, implying that release of Ca 2+ from internal stores caused by unoprostone further induced capacitative Ca 2+ entry. These results suggest that unoprostone-induced [Ca 2+ ] i increase in corneal endothelial cells results from Ca 2+ influx from external buffer and release of Ca 2+ from intracellular stores from the endoplasmic reticulum and mitochondria Ca 2+ stores followed by capacitative Ca 2+ entry. Unoprostone-induced intracellular Ca 2+ release was also modulated by phospholipase A 2 and C-coupled events.

In this study, the various antiglaucoma drugs including betaxolol, timolol, levobunolol, carteolol, brimonidine, dipivefrin, dorzolamide, brinzolamide, latanoprost, unoprostone, and pilocarpine were used to investigate the effects of cellular cytotoxicity in cultured bovine corneal endothelial cells. After exposure to the drugs in three dilutions, 1/100, 1/1,000, and 1/10,000, for 100 minutes, cells were estimated based on the release assay of lactate dehydrogenase (LDH) enzyme. It was found that cellular LDH was significantly released in the medium only at 1/100 th dilution of betaxolol, brimonidine, dorzolamide, dipivefrin, latanoprost and unoprostone to 130%, 123%, 145%, 157%, 128% and 237%, respectively, compared with controls upon exposure to drugs for 100 minutes. Moreover, benzalkonium chloride preservative at the concentrations ranging from 0.001 to 0.00001mg/mL did not affect cellular LDH release in bovine corneal endothelial cells. These results indicate that high concentrations of antiglaucoma drugs may induce cytotoxicity in corneal endothelial cells.

In the last decade topically applied prostaglandin F2alpha analogues (bimatoprost, latanoprost, travoprost and unoprostone) have become widely used as a means to reduce elevated intraocular pressure in patients with glaucoma and ocular hypertension. These molecules all have similar side-effect profiles, which include both side effects that occur frequently (e.g., conjunctiva hyperaemia, increase of iris pigmentation and eyelash changes) and rare adverse reactions (e.g., periocular pigmentation, damage to the blood-aqueous barrier and cystoid macular oedema). Conjunctiva hyperaemia, eyelash changes and cystoid macular oedema are reversible, but certain other side effects, such as increased iris pigmentation, are not. However, the systemic side-effect profile is favourable for all the prostaglandin analogues, and some of the local side effects are only of cosmetic significance. Numerous clinical studies suggest that discontinuing treatment with prostaglandin analogues on account of their side effects is rare in clinical practice.

Latanoprost and isopropyl unoprostone, which are analogues of prostaglandin F2alpha (PGF2alpha), are promising drugs for the reduction of intra-ocular pressure. However, they have been reported to have side effects, including hypertrichosis and hyperpigmentation of the eyelashes and periocular skin, and occasionally poliosis. In order to investigate these effects further, PGF2alpha, latanoprost and isopropyl unoprostone were applied to the dorsal skin of 7-week-old C57BL/6 mice, and hair length was measured during the treatment. The three molecules all showed stimulatory effects on the murine hair follicles and the follicular melanocytes in both the telogen and anagen stages, and stimulated conversion from the telogen to the anagen phase. PGE2 is known to act synergistically with PGF2alpha, and hence the influence of PGE2 was also examined. PGE2 did not induce distinct telogen-to-anagen conversion, but showed moderate growth stimulatory effects on early anagen hair follicles. In addition, we observed a case of hypertrichosis and trichomegaly with an excess of melanogenesis, leading to the emergence of white hair, suggesting that poliosis can occur as a side effect of eye treatment with solutions of PGF2alpha analogues. The stimulatory effects of PGF2alpha and PGE2 on hair growth have been discussed with regard to the role of protein kinase C and mast cells.

Background: The trabecular meshwork (TM) is a smooth muscle-like tissue with contractile properties and by this mechanisms involved in the regulation of aqueous humor outflow. Isopropyl unoprostone (Rescula®, Novartis Ophthalmics), a synthetic docosanoid, reduces intraocular pressure in glaucoma patients and normal subjects. In isolated TM strips, unoprostone reduces TM contractility in the presence of endothelin 1 (ET-1). However, the signal transduction pathway of unoprostone still remains unclear. Since L-type channel currents are known to influence the contractility of TM, we examined the effects of unoprostone and ET-1 on L-type channel currents of TM cells. Methods: The effects of unoprostone, ET-1 and the tyrosine kinase inhibitor herbimycin A on L-type channel currents of cultured human TM cells were investigated using the perforated patch configuration of the patch-clamp technique. Results: Application of ET-1 had no effect on L-type channel currents. Unoprostone led to a dose-dependent reduction of control currents. The effect of unoprostone is independent of ET-1. After preincubation of cells with herbimycin A, unoprostone had no effect on the L-type channel current amplitude. Human TM cells preincubated with herbimycin A showed a reduced current density compared with control cells. Both substances, unoprostone and herbimycin A, increased the inactivation time constant of L-type channel currents. Conclusion: We conclude that unoprostone reduces the activity of L-type Ca2+ channels. This effect seems to be independent of ET-1. The signal transduction pathway seems to be mediated by tyrosine kinases.

Over contraction of vascular smooth muscle may result in ischemia to ocular neuronal cells and deteriorate the glaucoma. The purpose of this study was to investigate the inhibitory effects of various commercial antiglaucoma drugs including brimonidine, dipivefrin, betaxolol, timolol, levobunolol, carteolol, brinzolamide, dorzolamide, unoprostone, latanoprost, pilocarpine, and preservative benzalkonium chloride on endothelin-1(ET-1) and KCl-induced increase of intracellular free Ca2+ ([Ca2+]i) in cultured rat A7r5 vascular smooth muscle cells. These drugs were diluted from original concentrations to 1/100, 1/1000, and 1/10000. [Ca2+]i mobility was analyzed by spectrofluorometry after loading with fura-2-AM. Betaxolol, timolol, levobunolol, and carteolol were found to inhibit KCl-induced release of [Ca2+]i in a dose-dependent manner. High concentrations of betaxolol, timolol, levobunolol, carteolol, and unoprostone also inhibited ET-1-induced increase of [Ca2+]i in A7r5 cells. However, ET-1- and KCl-induced increase of [Ca2+]i was not diminished by other drugs including brimonidine, dipivefrin, brinzolamide, dorzolamide, latanoprost, pilocarpine, and benzalkonium chloride. These results indicate that high concentrations of unoprostone and beta-adrenergic blocking agents including betaxolol, timolol, levobunolol, and carteolol may inhibit ET-1-induced increase of [Ca2+]i. The mechanism may be mediated by inhibition of extracellular calcium influx via blocking of L-type voltage-dependent Ca2+ channel in A7r5 cells.

To compare the efficacy and safety of brimonidine 0.2% vs unoprostone 0.15%, both added to timolol maleate 0.5% each given twice daily.In this prospective, multi-centred, double-masked, crossover comparison, patients were randomized to one treatment group for a 6-week treatment period, and then crossed over to the opposite treatment. Measurements were performed at 0800, 1000, 1600, 1800, and 2000 h at baseline and at the end of each treatment period.In all, 33 patients entered this trial and 29 completed. The baseline trough intraocular pressure (IOP) was 23.3+/-2.4 and the diurnal curve IOP was 22.0+/-1.3 mmHg. For the brimonidine and timolol maleate treatment group, the trough IOP was 21.6+/-3.3 and the diurnal curve IOP was 19.8+/-2.1 mmHg, while the timolol and unoprostone treatment showed a trough IOP of 20.9+/-3.8 and a diurnal curve IOP of 19.3+/-2.4 mmHg. There was no significant difference between treatment groups at any time point for the diurnal curve, or in the reduction from baseline (P0.05). Both treatments failed to statistically reduce the IOP from baseline at 1800 h. There was no difference between treatment groups regarding ocular and systemic unsolicited adverse events, but patients admitted to more dryness (P=0.02) and burning upon instillation (P0.0001) with unoprostone by survey.Brimonidine 0.2% or unoprostone 0.15% added to timolol maleate 0.5% provide similar efficacy and safety throughout the daytime diurnal curve.

Purpose: To compare the efficacy and safety of unoprostone versus brimonidine both given twice daily in ocular hypertensive or primary open-angle glaucoma subjects. Methods: After a 1-month washout period a baseline diurnal curve was measured every 2 hours from 08 : 00 hours (trough) to 20 : 00 hours in subjects with a trough intraocular pressure (IOP) and the pressure 24 mmHg. Qualified subjects were randomized to either brimonidine or unoprostone. After 6 weeks of treatment the period 1 diurnal curve was performed. Subjects were then switched to the opposite treatment for 6 weeks and the period 2 diurnal curve was performed. Results: A total of 33 subjects were included in this study. In the brimonidine-treated group the trough IOP 20.1 ± 2.8 mmHg was reduced from baseline up to 8 hours after dosing. In the unoprostone-treated group the trough IOP was 19.5 ± 3.0 mmHg, which was statistically equal to that of brimonidine (p = 0.21), was reduced from baseline for 12 hours after dosing. Brimonidine decreased the IOP statistically more than unoprostone at 10 : 00 and 12 : 00 hours (p

Unoprostone isopropyl is an ocular hypotensive that was originally produced as a prostaglandin F2alpha analogue and is eventually recognized as a synthetic docosanoid. The compound is recently suggested to have potent neuroprotective ability in the retina. The purpose of this study is to test whether and how the biologically active metabolites of unoprostone isopropyl rescue retinal neuro-glial progenitor cells from apoptosis.R28 cells were deprived of serum for 24 hr with or without varying concentrations of unoprostone metabolite M1 or M2 or vehicle in the presence or absence of specific inhibitors against several types of signal transduction proteins. Immunocytochemistry against activated caspase-3 with Hoechst nuclear staining was performed.Up to 15%of R28 cells became pyknotic and activated caspase-3 immunoreactive after 24-hr serum withdrawal. M1, but not M2, significantly reduced apoptotic cells in a dose-dependent fashion with a maximal effect at 100 microM (p.0001). LY294002, the phosphatidylinositol 3-OH kinase (PI3K) inhibitor, and KT5823, the protein kinase G (PKG) inhibitor, reversed the antiapoptotic effect of M1.The unoprostone metabolite M1 protects retinal neuro-glial progenitor R28 cells from apoptosis induced by serum deprivation via the PI3K and PKG pathways.

Based on the body of evidence implicating ocular blood flow disturbances in the pathogenesis of glaucoma, there is great interest in the investigation of the effects of antiglaucoma drugs and systemic medications on the various ocular vascular beds. The primary aim of this article was to review the current data available on the effects of antiglaucoma drugs and systemic medications on ocular blood flow. We performed a literature search in November 2002, which consisted of a textword search in MEDLINE for the years 1968-2002. The results of this review suggest that there is a severe lack of well-designed long-term studies investigating the effects of antiglaucoma and systemic medications on ocular blood flow in glaucomatous patients. However, among the 136 articles dealing with the effect of antiglaucoma drugs on ocular blood flow, only 36 (26.5%) investigated the effects of medications on glaucoma patients. Among these 36 articles, only 3 (8.3%) were long-term studies, and only 16 (44.4%) were double-masked, randomized, prospective trials. Among the 33 articles describing the effects of systemic medications on ocular blood flow, only 11 (33.3%) investigated glaucoma patients, of which only one (9.1%) was a double-masked, randomized, prospective trial. Based on this preliminary data, we would intimate that few antiglaucoma medications have the potential to directly improve ocular blood flow. Unoprostone appears to have a reproducible antiendothelin-1 effect, betaxolol may exert a calcium-channel blocker action, apraclonidine consistently leads to anterior segment vasoconstriction, and carbonic anhydrase inhibitors seem to accelerate the retinal circulation. Longitudinal, prospective, randomized trials are needed to investigate the effects of vasoactive substances with no hypotensive effect on the progression of glaucoma.

It has been postulated that endothelin-1 and nitric oxide (NO) could participate in the modulation of aqueous humor dynamic in the eye. This study investigates whether endothelin-1 can reduce the production of nitrite (a stable metabolite of NO) in isolated porcine ciliary processes. Nitrite production was measured (Griess reaction) in the medium surrounding isolated ciliary processes before and after exposure to different drugs. Results are expressed in percent of basal nitrite production. In a concentration-dependent manner (0.1 nM to 1 microM), endothelin-1 significantly decreased basal nitrite production (1 microM: 81.7+/-3.5%; P0.001). This effect was prevented by the endothelin type A (ETA)-receptor antagonist BQ123 (1 microM: 95.6+/-4.3%; P0.05), but not by the endothelin type B (ETB)-receptor antagonist BQ788 (1 microM: 83.3+/-4.4%; P=0.86) or by the prostaglandin F2alpha analog unoprostone (30 microM: 86.7+/-3.7%; P=0.74). The adenylcyclase activator forskolin significantly increased basal nitrite production (1 microM: 143.4+/-3.9%, P0.001). This effect was prevented both by endothelin-1 (0.1 microM; 113.9+/-6.7%: P0.01) or the nitric oxide synthase inhibitor L-NAME (0.5 mM: 103.3+/-8.4%: P0.001). The inhibitory effect of endothelin-1 on forskolin-induced nitrite production was significantly reversed by BQ123 (1 microM: 132.4+/-5.1%; P0.01), but not by BQ788 (1 microM: 112.7+/-4.1%; P=0.64) or unoprostone (30 microM: 109.3+/-4.8%; P=0.98). These results suggest that endothelin-1, through an ETA receptor activation, can reduce both basal and forskolin-induced nitrite production in isolated porcine ciliary processes.

BACKGROUND To investigate the vasoactive effect of bimatoprost (Lumigan), a new topical ocular hypotensive agent, in isolated porcine ciliary arteries. MATERIAL AND METHODS Arteries were placed in a myograph system to measure isometric forces. Quiescent vessels as well as vessels pre-contracted with either 10 nM endothelin-1 or 100 mM potassium chloride (KCl) were exposed, in a cumulative manner, to increasing concentrations (0.1 nM - 0.1 mM) of bimatoprost (dissolved in ethanol). In quiescent vessels, results were expressed in percent of 100 mM KCl-induced contraction. In endothelin-1-pre-contracted vessels, results were expressed in percent of the maximal contraction induced by endothelin-1. In KCl-pre-contracted vessels, results were expressed in percent of the plateau contraction reached 30 minutes after 100 mM KCl application. RESULTS Bimatoprost induced a significant (p < 0.05 - 0.001) vasoconstriction at concentrations equal to or higher than 0.1 micro M in quiescent vessels (0.1 mM: 73 +/- 12 %). In KCl-pre-contracted vessels, at concentrations higher than 1 micro M, bimatoprost induced significant (p < 0.05 - 0.01) contractions (0.1 mM: 67 +/- 17 %). In endothelin-1-pre-contracted vessels, bimatoprost also induced significant (p < 0.05 - 0.001) contractions at concentrations above 10 micro M (0.1 mM: 17 +/- 8 %). CONCLUSIONS The present study indicates that bimatoprost appears to have, in vitro, some vasoactive properties in porcine ciliary arteries. The question whether Lumigan has an influence on ocular blood flow needs to be further investigated.

Objective To compare the efficacy and safety of timolol 0.5%/dorzolamide 2% fixed combination vs timolol maleate 0.5% and unoprostone 0.15% given twice daily. Design Prospective multicenter, randomized, double-masked, crossover comparison study. Methods Primary open-angle glaucoma or ocular hypertension patients were randomly assigned to one of the treatment groups for a 6-week treatment period and then crossed over to the opposite treatment. Diurnal curve testing was performed at 8:00 am , 10:00 am , 4:00 pm , 6:00 pm , and 8:00 pm at baseline and the end of each treatment period. The run-in medicine was timolol twice daily for 28 days. Results Thirty-two patients completed this trial. The baseline trough pressure was 24.3 ± 3.0 mm Hg, and the diurnal curve was 23.4 ± 3.2 mm Hg. For the fixed combination the treatment trough pressure was 20.8 ± 4.1 mm Hg and the diurnal curve was 19.6 ± 3.6 mm Hg, whereas timolol and unoprostone concomitant therapy showed a treatment trough pressure of 20.1 ± 4.5 mm Hg and a diurnal pressure of 19.8 ± 4.1 mm Hg. There was no significant difference between treatment groups at any time point, for the diurnal curve, or in the extended reduction from baseline. There was no difference between treatment groups regarding ocular and systemic unsolicited or solicited adverse events. Burning, stinging, and conjunctival hyperemia were the adverse events most noted. There were no serious adverse events during this trial. Conclusions This study suggests that both timolol/dorzolamide 2% fixed combination and concomitant timolol maleate 0.5% and unoprostone 0.15% therapy provide similar efficacy and safety throughout the daytime diurnal curve.

Purpose: We have previously shown that the intra-ocular pressure (IOP) spike due to argon laser trabeculoplasty (ALT) is caused by an acute endothelin-1 (ET-1) release from the uveal tissue into the aqueous humour of rabbit eyes. In this study we investigated whether pretreatment with topical unoprostone isopropyl, a functional antagonist of ET-1, protects against the pressure spike due to ALT in the rabbit model. Methods: IOP of both eyes of 17 pigmented rabbits was measured with a TonoPen XL tonometer under general anaesthesia (baseline measurement). Then the right eyes were treated with topical unoprostone isopropyl 0.12% BID for 6 days, and the left eyes similarly received balanced salt solution (BSS) twice daily. After the last morning instillation, IOP for both eyes was measured under general anaesthesia after 2 h in group 1 and after 3 h in group 2 animals. Then, for both groups, ALT was performed on both eyes. Thirty minutes after laser treatment (and still under general anaesthesia), IOP was measured again. Then the aqueous humour was aspirated for measurement of ET-1 concentration. Results: Baselineindividual IOP differences (left eye minus right eye) were not significant in both groups: mean ± SD 0.25 ± 1.16 and –0.33 ± 0.71 mm Hg, respectively (paired t test, p > 0.05 for both groups). On day 6, 2 h (group 1) and 3 h (group 2) after the last instillation but before laser trabeculoplasty, the difference (BSS-pretreated left eye minus unoprostone-pretreated right eye) increased to 2.13 ± 2.10 mm Hg (p = 0.024) and 1.33 ± 0.71 mm Hg (p = 0.0005), respectively. Thirty minutes after ALT, the IOP difference was 2.63 ± 2.67 mm Hg in group 1 (p = 0.027), but no difference was seen in group 2 (0.67 ± 1.94 mm Hg, p = 0.332). In group 1, postoperative aqueous humour ET-1 concentration for the unoprostone-pretreated right eye was significantly lower than that for the BSS-pretreated left eye (paired t test, p = 0.01); but in group 2 no inter-ocular difference in ET-1 concentration was found (p = 0.976). Conclusion: Topical unoprostone pretreatment decreases laser-induced ET-1 release and diminishes the IOP spike caused by ALT in vivo within 2 h after instillation, when the concentration of unoprostone in the aqueous humour is high.

Latanoprost (Xalatan) is an ester analogue of prostaglandin F2alpha that reduces intraocular pressure (IOP) by increasing uveoscleral outflow. The IOP-lowering efficacy of latanoprost 0.005% lasts for up to 24 hours after a single topical dose, which allows for a once-daily dosage regimen. In patients with ocular hypertension or open-angle glaucoma, a single drop of latanoprost 0.005% solution (about 1.5 microg) administered topically once daily reduced diurnal IOP by 22 to 39% over 1 to 12 months' treatment in well-controlled trials; efficacy was maintained during treatment periods of up to 2 years. At this dosage, latanoprost was significantly more effective than timolol 0.5% twice daily in 3 of 4 large, double-blind, randomised studies, was generally as effective as bimatoprost or travoprost, and was significantly more effective than dorzolamide, brimonidine or unoprostone. Furthermore, in patients whose IOP was poorly controlled with timolol, switching to latanoprost monotherapy was at least as effective at lowering IOP as adding dorzolamide or pilocarpine to the regimen. Latanoprost has also shown significant additive effects when used in combination with one or more other glaucoma medications. The fixed combination of latanoprost plus timolol was significantly more effective than either of its individual components in two double-blind randomised studies and more effective than the fixed combination of dorzolamide and timolol in a 3-month, evaluator-masked study. Data in patients with angle-closure glaucoma are limited, but in patients with elevated IOP after undergoing iridotomy, latanoprost 0.005% once daily was significantly more effective than timolol 0.5% twice daily at reducing IOP over 12 weeks of treatment in a large double-blind, randomised study. Latanoprost is generally well tolerated and, unlike timolol, induces minimal systemic adverse events. In well-controlled, 6-month trials, the most commonly occurring drug-related ocular events in latanoprost recipients were mild to moderate conjunctival hyperaemia (3 to 15%) and iris colour change (2 to 9%); these seldom required patient withdrawal although the latter may be permanent. Latanoprost 0.005% as a single daily drop has shown good IOP-lowering efficacy in patients with open-angle glaucoma or ocular hypertension and does not produce the cardiopulmonary adverse effects associated with beta-blockers. Thus, latanoprost is a valuable addition to the first-line treatment options for patients with open-angle glaucoma or ocular hypertension. In addition, adjunctive treatment with latanoprost in patients who are refractory to beta-blocker therapy is a viable, second-line treatment option. Although preliminary findings are promising, wider clinical experience is required to define the place of latanoprost in the treatment of angle-closure glaucoma.

PURPOSE To compare the efficacy and safety of latanoprost versus isopropyl unoprostone (unoprostone) in Japanese patients with primary open-angle glaucoma (POAG) or ocular hypertension (OH). METHODS An 8-week, multicenter, randomized, comparative study was performed in 48 Japanese patients with POAG or OH. Four patients (two in each group) withdrew from the study, but their data were included in the safety assessment but not in the intraocular pressure (IOP) evaluation. The patients were randomly treated with latanoprost 0.005% once daily or unoprostone 0.12% twice daily for 8 weeks. IOP was measured at baseline and 2, 4, and 8 weeks after treatment. In addition, ocular and systemic adverse events were recorded. RESULTS The baseline IOPs were similar between the latanoprost (n = 25) and unoprostone (n = 19) groups (24.3 +/- 2.4 mm Hg vs 23.3 +/- 2.1 mm Hg, respectively, = 0.18). The IOP reductions from baseline at 2, 4, and 8 weeks after treatment were 5.8 +/- 2.4, 6.6 +/- 2.5, and 6.7 +/- 2.0 mm Hg in the latanoprost group, and 3.8 +/- 2.0, 3.5 +/- 2.3, and 3.3 +/- 3.0 mm Hg in the unoprostone group, respectively. The IOP reduction in the latanoprost group at 8 weeks was larger than that in the unoprostone group ( < 0.001, analysis of covariance). Five adverse events were observed in 4 (15%) of 27 patients in the latanoprost group, and five adverse events were observed in 4 (20%) of 21 patients in the unoprostone group. There was no difference in the incidence of adverse events between groups ( = 0.71). CONCLUSION Latanoprost produced a statistically greater reduction in IOP than unoprostone in Japanese patients with POAG or OH.

Purpose To compare the intraocular pressure (IOP)-lowering effect and safety of latanoprost 0.005% once daily with that of unoprostone 0.15% twice daily for patients with primary open-angle glaucoma or ocular hypertension. Design Randomized clinical trial. Methods In a prospective, 8-week, investigator-masked, parallel-group study conducted at numerous centers in the United States, 165 previously treated patients with IOP ≥ 25 mm Hg in one or both eyes after washout were randomly assigned to receive either latanoprost 0.005% once daily in the evening or unoprostone 0.15% twice daily. Observations procedures were Goldmann applanation tonometry, best-corrected visual acuity, slit lamp biomicroscopy, and ophthalmoscopy. The main outcome measure was change in the mean of the IOPs measured at 8:00 am, 12 noon, and 4:00 pm between baseline (before treatment) and after 8 weeks of treatment. Results The change in the mean ± SD of the IOPs measured at 8:00 am, 12 noon, and 4:00 pm was −7.2 ± 3.2 mm Hg (28%) for latanoprost (25.3 ± 2.8 mm Hg at baseline to 18.2 ± 2.8 mm Hg at 8 weeks) and −3.9 ± 2.6 mm Hg (15%) for unoprostone (25.5 ± 3.3 mm Hg at baseline to 21.6 ± 4.0 mm Hg; P ≤ .001. No serious adverse event related to either medication was reported. Conclusions Over an 8-week period, latanoprost 0.005% once daily lowered IOP more than unoprostone 0.15% twice daily in patients with elevated IOP. Both agents were safe and well tolerated.

Latanoprost, a prostaglandin F 2α analog prodrug, and unoprostone, an analog of a prostaglandin metabolite, have been shown to be effective in decreasing intraocular pressure when used alone or in combination with other ocular hypotensive agents. The increase in the uveoscleral outflow and some of the side effects are probably FP-receptor mediated, which may account for some differences between the cited drugs. This article reviews the recent literature available on the clinical efficacy of these prostanoids, as well as the studies directly comparing these drugs.

Purpose: To compare the cardiovascular effects of unoprostone 0.15%, timolol 0.5% and placebo in healthy adults during exercise using a treadmill test. Methods: Thirty subjects aged 18–37 years (mean age = 24.1 years) were randomized to one of six treatment sequences in a three-treatment, three-period crossover study (William's design). Study medication was instilled b.i.d. for 5 days before visits 2, 3, and 4. Between treatments, study medication was washed out for 9–10 days. Each subject underwent a submaximal treadmill test at visits 2 through 4, 15 min after dosing. Results: After 15 min of exercise, average heart rates were 143.1 ± 21.2, 134.5 ± 20.0 and 145.4 ± 20.8 bpm for the unoprostone, timolol and placebo treatments, respectively. At no timepoint was there a statistically significant difference between the unoprostone and placebo treatments (p > 0.05). Beginning with the second minute of exercise, timolol produced a greater decrease in heart rate at all timepoints from placebo than unoprostone (p 0.05). Conclusions: Unlike timolol, unoprostone 0.15% does not reduce exercise-induced heart rate, indicating a lack of clinical effect on systemic β-adrenergic receptors in young and healthy subjects.

Purpose: To investigate the long-term effect of 0.12% isopropyl unoprostone (Rescula®) on microcirculation in the human ocular fundus. Methods: A laser speckle tissue circulation analyzer was used to measure normalized blur (NB), a quantitative index of blood flow velocity, in the optic nerve head (ONH) and choroid-retina before and 4.5 hours after the instillation of a placebo into both eyes of 11 healthy volunteers. The intraocular pressure (IOP), blood pressure, and pulse rate were also recorded in this control experiment. Thereafter, a drop of unoprostone or a placebo was instilled into each eye in a double-blind manner twice a day for 21 days to form treated and untreated groups. Results: After 21 days, the NB values in the ONH and choroid-retina had increased significantly and the IOP had decreased significantly in the unoprostone-treated eyes. Ocular perfusion pressure showed no significant change. Conclusions: These results suggest that long-term application of unoprostone can increase microcirculatory blood flow in the human ocular fundus, probably due to a reduction in vascular resistance.