Unoprostone Research Articles

Unoprostone isopropyl rescues retinal progenitor cells from apoptosis in vitro

Purpose. Unoprostone isopropyl is an ocular hypotensive that was originally produced as a prostaglandin F2α 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.Methods. 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.Results. 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 μM (p <. 0001). LY294002, the phosphatidylinositol 3-OH kinase (PI3K) inhibitor, and KT5823, the protein kinase G (PKG) inhibitor, reversed the antiapoptotic effect of M1.Conclusions. The unoprostone metabolite M1 protects retinal neuro-glial progenitor R28 cells from apoptosis induced by serum deprivation via the PI3K and PKG pathways.

Vasodilatory mechanism of unoprostone isopropyl on isolated rabbit ciliary artery

Purpose. To clarify the vasodilatory mechanism of unoprostone isopropyl (unoprostone), a PG F2a related compound used for treatment of glaucoma, we have investigated the effect of this drug and its metabolites on isolated rabbit ciliary artery in vitro. Methods. Under the dissecting microscope, ciliary arteries were prepared from albino rabbit eyes and mounted in a myograph system. The effects of unoprostone isopropyl and other agents were investigated using isometric tension recording methods. Results. Unoprostone induced a dose-dependent relaxation in ciliary arteries that were pre-contracted with high-K solution, 10µM histamine or 10µM PG F2a. Neither unoprostone metabolite M1 or M2 had a relaxant effect on the precontracted vessels. Relaxation was unaffected by inhibition of adenylyl cyclase with SQ 22536, guanylyl cyclase with ODQ, or maxi-K channels with iberiotoxin. Pretreatment with unoprostone did not affect histamine-induced transient contractions in Ca 2+ -free solution. However, SKF96365, a general Ca 2+ channel blocker, evoked relaxation similar to unoprostone with respect to amplitude and rate of onset. Conclusions. Unoprostone, but not its metabolites M1 and M2, relaxed pre-contracted rabbit ciliary artery. The mechanism of vascular smooth muscle relaxation by unoprostone differs from that of IOP reduction and does not depend on adenylyl cyclase, guanylyl cyclase, or maxi-K channels. Relaxation may be mediated by inhibition of Ca 2+ entry, possibly through capacitative Ca 2+ channels.

Custo do tratamento de drogas antiglaucomatosas: latanoprost, travoprost, bimatoprost e unoprostona isopropílica

OBJETIVO: Determinar o custo do tratamento clínico antiglaucomatoso com drogas de ação úveo-escleral considerando o numero de gotas por frascos, volume médio das gotas assim como a duração máxima do tratamento propiciada por frasco. MÉTODOS: Realizou-se estudo experimental utilizando oito frascos de cada espécie de quatro colírios antiglaucomatosos: latanoprost, travoprost, bimatoprost e unoprostona isopropílica. Mediram-se o número e volume médio das gotas por frasco de colírio, calculando-se a duração e custo do tratamento antiglaucomatoso. RESULTADOS: O número médio de gotas por frasco variou amplamente nos quatro produtos estudados: latanoprost, com média de 110,87 (±5,35) gotas por 2,5 ml exibiu a contagem mais elevada, seguido do travoprost com 102,62 (±4,27) gotas, enquanto que o bimatoprost com 90,93 (±3,77) gotas por 2,5 ml exibiu a contagem mais baixa. O volume médio da gota para o grupo das quatro medicações foi de 25,13 µl. Em relação à duração da terapêutica, o latanoprost e o travoprost durariam mais com respectivamente 55,43 e 51,31 dias enquanto o bimatoprost e unoprostona isopropílica durariam menos, 45,45 e 45,72 dias. Observou-se que a unoprostona isopropílica apresentou o menor custo diário R$ 0,81. Quanto ao tratamento durante o período de um ano, verificou-se: latanoprost, custo anual variando entre R$ 335,80 a 463,23, travoprost, R$ 306,60 a 427,05, bimatoprost, R$ 372,30 a 496,40 e unoprostona isopropílica, R$ 211,70 a 295,65. CONCLUSÃO: Este estudo sugere que existem marcadas diferenças no custo diário entre as drogas de ação úveo-escleral.

Unoprostone isopropyl ester darkens iris color in pigmented rabbits with sympathetic denervation.

Unoprostone isopropyl ester (unoprostone) -induced iris color darkening was evaluated in a rabbit model using a cyclooxygenase inhibitor, an alpha(1)-adrenergic antagonist, and sympathetic denervation. Dutch-belted rabbits were divided into five groups based on type of surgery and eyedrop treatment to both eyes: (1) sham surgery (n = 7); (2) bilateral superior cervical ganglionectomy (SCGx, n = 7); (3) SCGx plus flurbiprofen 0.03% (n = 7); (4) SCGx plus thymoxamine 0.5% (n = 6); and (5) SCGx plus flurbiprofen and thymoxamine (n = 6). All rabbits were treated with unoprostone 0.12% to one eye and its vehicle to the contralateral eye twice daily for 43 weeks after SCGx. Periodic color photographs of paired eyes were scored for difference in eye color. Iris melanin and aqueous humor protein were measured at week 43. Twenty-three of the 26 rabbits with bilateral SCGx and unilateral unoprostone treatment demonstrated a darker iris color on the unoprostone-treated side. The average scores (demonstrating difference in iris color) comparing photographs of treated versus control eyes in the four SCGx groups were higher than those in the sham surgery group (P < 0.03), and higher than at week 0 (P < 0.001). The group pretreated with flurbiprofen and thymoxamine had the highest score of all groups. The aqueous humor protein in unoprostone-treated eyes was higher (P < or = 0.0001) than in vehicle-treated eyes. The melanin content of irides of the denervated groups was higher (P < or = 0.01) in unoprostone-treated than in vehicle-treated eyes. Unoprostone produced iris color darkening in pigmented rabbit eyes with sympathetic denervation. Pretreatment with flurbiprofen and thymoxamine appeared to enhance this effect but this was not statistically demonstrated by the study.

Unoprostone Isopropyl Pretreatment Decreases Endothelin-1 Release and the Intra-Ocular Pressure Spike Induced by Laser Trabeculoplasty in the Rabbit

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.

Safety of Unoprostone Isopropyl 0.15% Ophthalmic Solution in Patients with Mild to Moderate Asthma

Purpose: To assess the safety of unoprostone isopropyl 0.15% ophthalmic solution (UIOS) in patients with mild to moderate asthma. Methods: Randomized, double-masked, two-period crossover, placebo-controlled study comparing unoprostone 0.15% with vehicle-placebo. Pulmonary function tests conducted at baseline and during the 4-hour postdose observation period included forced expiratory volume in 1 s, forced vital capacity, peak expiratory flow rate, and bronchodilator response after 200 µg inhaled salbutamol. Results: There were no significant changes in pulmonary function up to 4 h postdose after treatment with 1 drop unoprostone 0.15% in each eye. Conclusion: Unoprostone 0.15% was safe for use in patients with mild to moderate asthma, without affecting the response to bronchodilator therapy.

Cystoid Macular Edema Associated with Latanoprost Use in a Pseudophakic Eye with a History of Surgical Complications

Purpose: To report the development of cystoid macular edema following the use of topical latanoprost in an eye with glaucoma and pseudophakia. Case: A 73-year-old woman with bilateral pseudophakia and glaucoma had been treated with topical carteolol hydrochloride and isopropyl unoprostone bilaterally. One month later the unoprostone was replaced by latanoprost bilaterally. After 1 month, the patient complained of decreased vision in the right eye, which had a history of surgical complications. Results: Fluorescein angiography showed cystoid macular edema in the right fundus. The edema disappeared 2 weeks after the discontinuation of latanoprost. Cystoid macular edema did not develop in the left eye, which had no history of surgical complications. Conclusion: These observations suggest that latanoprost may cause cystoid macular edema in an eye with a history of surgical complications.

Human Trabecular Meshwork Cell Responses Induced by Bimatoprost, Travoprost, Unoprostone, and other FP Prostaglandin Receptor Agonist Analogues

To determine the functional agonist potencies of the intraocular pressure (IOP)-lowering prostaglandin F (FP)-class prostaglandin (PG) analogues (e.g., travoprost, latanoprost, bimatoprost, and unoprostone isopropyl ester) in human trabecular meshwork (h-TM) cells, by using phosphoinositide (PI) turnover and intracellular Ca(2+) ([Ca(2+)](i)) mobilization, and to confirm the FP nature of these receptors by using an FP receptor antagonist, 11beta-fluoro-15-epi-15-indanyl-PGF(2alpha) (AL-8810). FP-receptor-mediated PI turnover and [Ca(2+)](i) mobilization were measured in h-TM cells by determining the accumulation of [(3)H]-inositol phosphates ([(3)H]-IPs) by anion-exchange chromatography and real-time fluorescence imaging, respectively. Various PG analogues concentration-dependently stimulated production of [(3)H]-IPs in h-TM cells with the following agonist potencies (median effective concentration; EC(50)): travoprost acid (EC(50) = 2.4 nM) > cloprostenol (EC(50) = 4.5 nM) > (+/-)-fluprostenol (EC(50) = 10.8 nM) > latanoprost acid (EC(50) = 34.7 nM) > bimatoprost acid (EC(50) = 112 nM) > PGF(2alpha) (EC(50) = 120 nM) >> unoprostone (UF-021; EC(50) = 3280 nM) > S-1033 (EC(50) = 4570 nM; all n = 3-9). Prodrug derivatives of these compounds exhibited the following potencies: travoprost (isopropyl ester; EC(50) = 89.1 nM) > latanoprost (isopropyl ester; EC(50) = 778 nM) > bimatoprost (amide; EC(50) = 1410-6940 nM). Travoprost acid, PGF(2alpha,) unoprostone, and S-1033 were tested in addition for [Ca(2+)](i) mobilization and found to have rapid and dose-dependent effects. The FP receptor-selective antagonist AL-8810 antagonized the (+/-)-fluprostenol-induced PI turnover in these cells (K(i) = 2.56 +/- 0.62 micro M) as well as that induced by bimatoprost and acids of latanoprost and travoprost. The agonist and antagonist potencies of the PG analogues from the PI turnover assays in h-TM cells correlated well with PI turnover data obtained from the cloned human ciliary body FP receptor (r = 0.92; P < 0.0001). The pharmacology of the h-TM cell FP-receptor-mediated PI turnover and [Ca(2+)](i) mobilization was defined using numerous synthetic (FP-selective) PG agonist analogues and an FP receptor antagonist, AL-8810. Bimatoprost, travoprost, latanoprost, unoprostone isopropyl ester, and their respective free acids were shown to be FP agonists in the h-TM cells.

Pharmacological mechanisms, clinical effectiveness, and side-effects of prostaglandin analogues as anti-glaucoma agents

Prostaglandin (PG)-related ophthalmic solutions, which only recently became available for clinical use, are currently the most widely used solutions in the treatment of glaucoma, because they have excellent ocular hypotensive effects with little adverse effects. With respect to the pharmacological mechanism of action of these solutions, the mechanism of intraocular pressure (IOP) reduction for latanoprost, the first drug in this class to become available, is to promote the outflow of aqueous humor through the uveoscleral route, an important aqueous humor outflow tract. Molecular and cellular studies have shown that latanoprost affects the extracellular matrix metabolism in the uveoscleral route. For other PG-related ophthalmic solutions, there is no consensus opinion on their effects on the aqueous humor outflow tract, and how they reduce the IOP remains largely unclear. The docosanoid, isopropyl unoprostone, has excellent ocular hypotensive effects, despite having extremely low affinities to the known PG receptors. Many basic and clinical studies have demonstrated that PG-related ophthalmic solutions themselves cause not only a decrease in the IOP, but also induce endogenous PGs which could lead to secondary effects that may account in part for the IOP reduction. PG-related ophthalmic solutions have essentially no clinically important systemic adverse effects, but often have local adverse effects. The most characteristic is the pigment deposition in the iris or eyelid. Corneal epitheliopathy is also relatively common. In addition, as an adverse effect that affects vision, cystoid macular edema can be seen. Current studies are aimed at elucidating the mechanisms of development of these adverse effects, and thus to establish measures to prevent them. We compare the mechanisms of action of PG-related ophthalmic solutions and review the adverse effects and their mechanisms. Biomedical Reviews 2002; 13: 17-27.

New glaucoma medications in the geriatric population: efficacy and safety.

Glaucoma can be considered a disease of the aging eye. Most medications used to treat glaucoma are in topical eyedrop form and may cause numerous untoward systemic effects in older persons. In recent years, several new ocular hypotensive medications have become available. These medications are being used more commonly because there is a growing trend by ophthalmologists to aggressively lower intraocular pressure. Therefore, geriatricians require a comprehensive knowledge of medications used to treat glaucoma, in addition to an understanding of their mechanism of action profiles of untoward effects and possible interactions with other diseases or medications. Therefore, we performed a review of the medications recently introduced into clinical practice. We selected drugs approved by the U.S. Food and Drug Administration between 1996 and September 2001. The safety profiles of these agents and their untoward side effects were reviewed by class: topical carbonic anhydrase inhibitors (brinzolamide: ocular tolerance, taste perversion), beta-adrenoceptor antagonists (timolol: bradycardia and bronchospasm), alpha-adrenergic agonists (brimonidine: oral dryness, headache, and fatigue), and prostaglandin analogs (latanoprost, bimatoprost, travoprost, and unoprostone isopropyl: ocular hyperemia, iris color changes). The function of this review is to make geriatricians more aware of the efficacy and untoward effects of medications recently introduced into clinical practice. We recommend that geriatricians perform a medication review on all medications their patients use, including eye drops.

Autoantibody against neuron-specific enolase found in glaucoma patients causes retinal dysfunction in vivo.

In our recent paper, we have reported the presence of serum autoantibody against neuron-specific enolase (NSE) in patients with glaucoma. The purpose of the present study was to investigate further the pathological effects of anti-NSE antibody on retina by comparing them with the effects induced by N-methyl-D-aspartate (NMDA). Either a glaucoma patient's serum or purified anti-NSE antibody, or 10-40 mM NMDA was intravitreously administered into Lewis rat eyes, and electrophysiological, histopathological, and biochemical evaluations were performed. In addition, the neuroprotective effects of anti-glaucoma drugs, such as timolol, betaxolol, nipradilol, and isopropyl unoprostone, and a calcium antagonist were also studied using these animal models. Electron microscopy revealed that intravitreal administration of a glaucoma patient's serum, which immunoreacted with retinal 50 kDa in Western blot analysis, and purified anti-NSE antibody induced retinal ganglion cell apoptosis in rat eyes. Functionally, these eyes showed a significant decrease in electroretinogram (ERG) responses and a remarkable decrease in rhodopsin phosphorylation reaction. These changes were comparable to the effects observed after the intravitreal administration of 20 mM NMDA. Co-administration of nipradilol, an alpha- and beta-blocker, with anti-NSE antibody or 20 mM NMDA caused marked recovery of the affected ERG responses within 2 weeks. In contrast, administration of timolol or betaxolol showed no recovery effect on the ERG responses. Among these drugs, only betaxolol showed a recovery effect on NMDA-induced decrease of rhodopsin phosphorylation. Nilvadipine functioned beneficially on both impaired ERG and rhodopsin phosphorylation reactions observed in rat eyes injected intravitreously with anti-NSE antibody or NMDA. These effects of nilvadipine were not changed by the addition of endothelin-1. In contrast, isopropyl unoprostone had no effect on these functions. These observations suggest that serum autoantibody against NSE found in some patients with glaucoma induces retinal dysfunction in vivo, similarly to NMDA.

Effects of Isopropyl Unoprostone, Latanoprost, and Prostaglandin E2 on Acute Rise of Aqueous Flare in Pigmented Rabbits

Purpose: To evaluate the effect of isopropyl unoprostone, latanoprost, and prostaglandin E₂ (PGE₂) on aqueous flare elevation. Methods: Isopropyl unoprostone (0.12%) or latanoprost (0.005%) was topically instilled. Transcorneal diffusion of PGE₂, 25 µg/ml, using a glass cylinder, was achieved in pigmented rabbits. Aqueous flare was measured with a laser flare cell meter. Results: Topical instillation of isopropyl unoprostone induced aqueous flare elevation in rabbit eyes. Also, topical isopropyl unoprostone additionally induced aqueous flare elevation in eyes with transcorneal diffusion of PGE₂. Latanoprost did not induce flare elevation. Conclusion: Isopropyl unoprostone induced aqueous flare elevation in rabbits, and latanoprost did not produce aqueous flare elevation.

Comparison between Isopropyl Unoprostone and Latanoprost by Prostaglandin E2Induction, Affinity to Prostaglandin Transporter, and Intraocular Metabolism

The pharmacological differences between isopropyl unoprostone (referred to as unoprostone) and latanoprost, concerning their induction of endogenous prostaglandin E2(PGE2) and affinity to a human prostaglandin transporter (PGT), were investigated.Freshly dissected bovine iris tissues were incubated with major intraocular metabolites of unoprostone, M1 and M2, acid of latanoprost, or PGF2 α, and PGE2induction was measured. Affinities of M1, M2, latanoprost, acid of latanoprost, and PGF2αto PGT molecule were measured using PGT-cDNA transfected HeLa cells by an isotopic influx assay.3H-unoprostone was incubated with freshly prepared serum, aqueous humor, or frozen stored fetal bovine serum (FBS), and the radioactivity of supernatants was measured to investigate their metabolism of3H-unoprostone.M2, acid of latanoprost, and PGF2 αsignificantly increased a release of PGE2compared with the control. 10μM indomethacin completely inhibited PGE2induction by acid of latanoprost and PGF2 α, while 100μM indomethacin was required to inhibit PGE2induction completely by M1 and M2. Unoprostone, M1, M2, and latanoprost showed little affinity to PGT, while acid of latanoprost had an affinity to PGT. Freshly prepared serum and aqueous humor metabolized unoprostone, but frozen stored FBS did not. The release of endogenous PGE2may play an important role of action by means of PG analogs, and differences in indomethacin-related inhibition of PGE2release and in affinities to PGT may in part cause their different actions.

Safety of unoprostone isopropyl as mono- or adjunctive therapy in patients with primary open-angle glaucoma or ocular hypertension.

This review summarises the safety of unoprostone isopropyl (both at the 0.12 and 0.15% concentrations) instilled twice daily in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OH). For unoprostone 0.15%, combined data from two 12-month comparative monotherapy studies are reported, as well as data from three adjunctive therapy studies and two special population studies. With unoprostone monotherapy, most adverse events were mild or moderate and transient in nature. Less than 7% of unoprostone-treated patients discontinued therapy due to an adverse event. The most common adverse events associated with unoprostone were burning/stinging, burning/stinging directly upon drug instillation, ocular itching, and conjunctival hyperaemia. Unoprostone had no clinically notable effects on vital signs, laboratory profiles, or comprehensive ophthalmic examinations. One of 659 unoprostone 0.15%-treated patients had a change in iris colour after 12 months of monotherapy. Except for a higher incidence of burning/stinging and burning/stinging upon instillation, unoprostone was comparable to timolol 0.5% twice daily and betaxolol 0.5% twice daily. No safety concerns were raised with use of unoprostone as adjunctive therapy. Unoprostone had no significant effect on exercise-induced heart rate in healthy subjects or on pulmonary function in patients with mild-to-moderate asthma. The safety profile of unoprostone 0.15% was consistent with published information on the 0.12% formulation. In conclusion, unoprostone has an excellent safety profile in patients with POAG or OH.

A double-masked randomized comparison of the efficacy and safety of unoprostone with timolol and betaxolol in patients with primary open-angle glaucoma including pseudoexfoliation glaucoma or ocular hypertension. 6 month data

PURPOSE: A long-term comparison of the ocular hypotensive efficacy and safety of unoprostone isopropyl 0.15% twice daily with that of timolol maleate 0.5% twice daily and betaxolol HCl 0.5% twice daily. DESIGN: This was a randomized, multicenter, double-masked, active-controlled 24-month clinical trial involving 27 centers in Europe and Israel. METHODS: The study population was composed of patients with primary open-angle glaucoma (including pseudoexfoliation) or ocular hypertension. After washout of antiglaucoma medications, intraocular pressure (IOP) was measured at 0, + 2, + 8, and + 12 hours. Patients were randomized in a 2:1:1 ratio to unoprostone, timolol, or betaxolol. Patients returned for examinations at 2 and 6 weeks and 3 and 6 months. RESULTS: 556 patients were randomized. Each drug produced a clinically and statistically ( P < .001) significant reduction from baseline in 12-hour diurnal IOP at month 6 (− 4.3 mm Hg, unoprostone; − 5.8 mm Hg, timolol; − 4.9 mm Hg, betaxolol). Differences in adjusted treatment means between unoprostone and timolol and unoprostone and betaxolol were 1.57 mm Hg (95% CI: 1.00, 2.13) and 0.53 mm Hg (95% CI: − 0.03, 1.09), respectively. Unoprostone was clinically equivalent to betaxolol but did not have as great an IOP-lowering effect as timolol. Discontinued for inadequate control of IOP were 7%, 1%, and 4% of the patients for unoprostone, timolol, and betaxolol, respectively. There were no changes of note in visual acuity, pupil size, cup-to-disk ratio, visual fields, or iris color. Changes in heart rate and blood pressure were small, with no clinically significant differences between groups. CONCLUSIONS: Unoprostone provided a clinically significant IOP-lowering effect equivalent to betaxolol but not to timolol. The side effect profile of unoprostone appears to be comparable to other established IOP-lowering agents.

A Comparison of Intraocular Pressure-Lowering Effect of Prostaglandin F2-?? Analogues, Latanoprost, and Unoprostone Isopropyl

To compare the intraocular pressure-lowering effect of unoprostone isopropyl (unoprostone) 0.12% and latanoprost 0.005%. A correlation between the intraocular pressure-lowering effect of unoprostone and latanoprost was also evaluated. A single-masked randomized study included 18 patients between 49 and 68 years (mean, 60.7 +/- 5.1 years) with an intraocular pressure of both eyes from 21 to 27 mm Hg. The patients were prospectively randomized to receive latanoprost in the right eye and unoprostone in the left eye, or unoprostone in the right eye and latanoprost in the left eye. The patients were followed up for 8 weeks. This study evaluated the intraocular pressure-lowering effect and incidence of drug-related side effects. Mean baseline intraocular pressure was 22.8 +/- 1.2 mm Hg in latanoprost-treated eyes and 22.4 +/- 1.0 mm Hg in unoprostone-treated eyes; there was no statistically significant difference between these groups. Mean intraocular pressure at 8 weeks after the start of the administration was 16.7 +/- 2.0 mm Hg in latanoprost-treated eyes and 19.0 +/- 1.5 mm Hg in unoprostone-treated eyes. Patients in the latanoprost-treated group showed a greater intraocular pressure reduction compared with those in the unoprostone-treated group. Mean intraocular pressure changes in latanoprost-treated eyes were significantly greater at every visit (P < 0.0001). A change of intraocular pressure at 8 weeks in the latanoprost-treated eyes was significantly correlated with that in the contralateral unoprostone-treated eyes (r = 0.665, P = 0.0013) (Figure). There was no significant difference in the rate of ocular side effects between latanoprost- and unoprostone-treated eyes. Latanoprost appears to have a more beneficial effect for intraocular pressure control compared with unoprostone. An intraocular pressure reduction in the latanoprost-treated eyes was significantly correlated with that in the contralateral unoprostone-treated eyes. There was no significant difference in the incidence of ocular side effects between both drugs. Further investigation using more cases and longer follow-up periods are needed.

Studies on receptor binding and signal transduction pathways of unoprostone isopropyl.

We examined the binding characteristics of unoprostone isopropyl and its metabolite, M1 (M1), in bovine corpus luteum membranes, mobilization of intracellular calcium in human ciliary muscle cells and cyclic AMP generation in rabbit iris-ciliary body. The ligand binding assay of 3H-unoprostone isopropyl and M1 did not demonstrate any specific binding of these compounds in the bovine corpus luteum membranes. However, there was a high specific binding of prostaglandin F2alpha. Competitive ligand binding studies showed that neither the docosanoid, unoprostone isopropyl, nor M1 binds to prostaglandin receptor sites. In human ciliary muscle cells that express EP1, EP2 and FP receptors, unoprostone isopropyl did not increase the mobilization of intracellular calcium nor was it able to generate cyclic AMP at low concentrations in rabbit iris-ciliary body. Similar observations were made with M1 on the above signal transduction pathways. From these results, it is concluded that unoprostone isopropyl and M1 do not bind to prostaglandin (PG) receptor sites in the bovine corpus luteum membranes and do not have affinity for PG receptors linked to intracellular calcium and cyclic AMP second messenger systems.

Effects of Isopropyl Unoprostone on Melanogenesis in Mouse Epidermal Melanocytes

Purpose: To investigate the effects of isopropyl unoprostone (referred to as unoprostone) on melanin synthesis and the nature of melanin. Methods: M1 and M2, potential intraocular oxidized metabolites of unoprostone, were added to the culture medium in a cultured immortal line of mouse epidermal melanocytes, melan-a, once a day for 2 weeks at concentrations of 5 nM and 50 nM. Vehicle solution was utilized as a control. The amounts of pyrrole-2,3,5-tricarboxylic acid (PTCA), an oxidized product of eumelanin, and aminohydroxyphenylalanine (AHP), a hydrolyzed product of pheomelanin, were measured by high-performance liquid chromatography. Results: A 5-nM concentration of M2 significantly increased PTCA production (20.84 ± 3.17 ng/10 6 cells mean ± SD) compared with the control (14.58 ± 4.62 ng/10 6 cells) ( P = .04), although other concentrations did not affect the synthesis of PTCA or AHP. A 5-nM concentration of M2 significantly increased the PTCA/AHP (1.86 ± 0.18) ratio compared with the control (1.37 ± 0.41) ( P = .04). A 50 nM concentration of M2 slightly increased the PTCA/AHP (1.74 ± 0.58) ratio, but M1 did not affect this ratio. Conclusions: These results indicate that M2 affects not only melanogenesis but also the nature of melanin, which could result in unoprostone-generated iridial pigmentation.

Effects of topical unoprostone and latanoprost on acute and recurrent herpetic keratitis in the rabbit

PURPOSE: To determine the effect of the topical ocular hypotensive drug, isopropyl unoprostone, a docosanoid molecule with very weak prostaglandin activity, on herpes keratitis in the rabbit eye. METHODS: For acute disease, rabbit corneas inoculated with the corticosteroid-sensitive F(MP)E strain of herpes simplex virus type 1 were treated with various combinations of 0.12% isopropyl unoprostone, latanoprost, trifluridine, benzalkonium chloride 0.02%, dexamethasone sodium phosphate, ketorolac tromethamine, or saline solution beginning 1 day after infection. Severity of keratitis was evaluated in a masked manner. For recurrent disease, rabbit corneas infected with McKrae strain herpes simplex virus type 1 were treated with unoprostone or saline solution on postinfection days 25 to 42, and the presence or absence of lesions was recorded. RESULTS: Eyes treated with unoprostone showed significantly less severe disease than saline-treated or latanoprost-treated eyes during acute infection. Unoprostone-treated and saline-treated eyes showed no significant difference in the frequency of recurrent lesions. Eyes treated with latanoprost and/or dexamethasone, separately or in combination, showed increased severity of acute herpes simplex virus keratitis, whereas benzalkonium chloride 0.02%–treated eyes showed no significant difference, compared with saline treatment. Trifluridine resulted in rapid healing. CONCLUSIONS: Unoprostone did not increase the severity or recurrence rate of herpes simplex virus keratitis. Unoprostone requires twice-a-day administration, compared with once-a-day for latanoprost, and unoprostone lowers intraocular pressure less than latanoprost. Nevertheless, unoprostone’s superior safety profile may make its use advantageous. Benzalkonium chloride alone did not make the keratitis worse.

Effects of Isopropyl Unoprostone Ophthalmic Solution on Cultured Rabbit Corneal Epithelial Cells

Purpose: To investigate the effects of isopropyl unoprostone (referred to as unoprostone) ophthalmic solution on the barrier function of cultured rabbit corneal epithelium grown on permeable supports. Methods: Rabbit corneal epithelial cells cultured on collagen-coated filter inserts were administered one of the following for 30 min: unoprostone in vehicle solution (polysorbate 80), unoprostone in vehicle solution with a preservative (benzalkonium chloride), preservative only or vehicle only. For a control, no chemicals were added to the medium. After administration, the transepithelial electrical resistance (TER) measurement, a sensitive method by which to investigate the barrier function, and morphological observation using phase-contrast microscopy were performed before exposure and at 0.5, 1, 3, 6, 12, 24, 48 and 72 h after exposure. The transmission electron-microscopic observation was performed before and 72 h after exposure in all experimental conditions. Results: The cells exposed to unoprostone with the preservative showed a significant decrease in the TER, although no morphological changes were observed. The corneal epithelial cells exposed to unoprostone without preservative, the vehicle only or the preservative only did not show any differences from the control group at any measurements. Conclusion: The corneal barrier function is damaged by a combined solution of unoprostone and preservative, but not by a single solution of unoprostone, in vitro.