Efficacy and Safety of Omidenepag Isopropyl 0.002% Ophthalmic Solution: A Retrospective Analysis of Real-World Data in Japan.

INTRODUCTION: This study aimed to clarify the efficacy and safety of omidenepag isopropyl (OMDI) in a retrospective, real-world, multicenter setting. METHODS: A retrospective medical chart review of patients with glaucoma and ocular hypertension receiving OMDI from November 2018 to November 2019 with at least 12 weeks of follow-up was conducted in 11 eye clinics in Japan. The participants were categorized into three therapy groups, designated the naïve monotherapy, switching monotherapy, and concomitant therapy groups. The main outcome measures were the change in intraocular pressure (IOP) at week 4 and week 12 after the initiation of OMDI treatment, and frequency of adverse drug reactions. RESULTS: Data were collected from 827 patients. The baseline IOP in the naïve group was 16.6 ± 4.2 mmHg. The mean IOP reduction at week 4 and week 12 was - 2.9 ± 3.2 mmHg (P < 0.0001) and - 2.5 ± 2.9 mmHg (P < 0.0001), respectively. Eyes with baseline IOP less than 16 mmHg also showed a significant reduction of IOP of - 1.4 ± 2.0 mmHg at week 12. OMDI significantly reduced IOP not only in eyes with primary open-angle glaucoma but also in eyes with primary angle-closure glaucoma and secondary glaucoma. In the switching monotherapy group, IOP did not change significantly after switching from most classes of medications to OMDI, but further IOP reduction was observed in the case of switching from beta-blockers to OMDI. The frequency of adverse drug reactions was 14.1% in all participants, and the most common adverse reaction was ocular hyperemia (7.6%). No serious and severe side effects were observed in this study. CONCLUSION: OMDI showed an IOP-lowering effect in eyes with various types of glaucoma and using various therapeutic regimens in real-world clinical practice. In addition, OMDI did not show any serious and severe side effects, suggesting the potential of OMDI as a first-line medicine for the treatment of glaucoma. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN): 000040040.

Twenty-Four-Hour Intraocular Pressure Control with Omidenepag Isopropyl 0.002% in Patients with Glaucoma and Ocular Hypertension.

PURPOSE: To clarify the intraocular pressure (IOP)-lowering effect of a selective prostanoid EP2 receptor agonist, omidenepag isopropyl (OMDI) during a 24-hour period. PATIENTS AND METHODS: Subjects aged ≥20 years and with diagnosed, untreated primary open-angle glaucoma or ocular hypertension were enrolled. IOP measurements were performed every 4 hours over a 24-hour period using a Goldmann applanation tonometer (GAT) and Icare PRO tonometer (PRO). The baseline 24-hour IOP was measured in untreated subjects. After the baseline measurements, participants were given OMDI 1 drop once daily at night for 4 weeks. At week 4, the IOP measurement was repeated under the same conditions. Diurnal (9 am, 1 pm, 5 pm) and nocturnal (9 pm, 1 am, 5 am) IOP measurements were compared between baseline and treatment with OMDI. Safety measures included adverse events, slit-lamp biomicroscopy, visual acuity, heart rate and blood pressure. RESULTS: Of 27 participants enrolled, 25 patients (20 males and 5 females, average age 52.2 ± 8.5 years) completed the study. In the sitting position, the baseline diurnal and nocturnal mean IOPs (GAT) were 19.1 ± 2.1 mmHg and 18.2 ± 2.6 mmHg, respectively, the diurnal and nocturnal mean IOP reduction from baseline were -2.8 ± 2.6 mmHg (p < 0.0001) and -3.3 ± 2.9 mmHg (p < 0.0001), respectively, mean 24-hour IOP (GAT) was significantly lower with the OMDI treatment (-3.1 ± 2.5 mmHg, p < 0.0001). In the supine position, the baseline nocturnal mean IOP (PRO) was 17.99 ± 2.22 mmHg, and the nocturnal mean IOP reduction from baseline was -1.78 ± 2.37 mmHg (p = 0.0009) after 4 weeks of the treatment. Nine adverse events were observed in 8 patients including mild conjunctival hyperemia (n = 8) and mild iritis (n=1). There were no significant effects on systemic safety. CONCLUSION: Once daily OMDI treatment was able to produce stable 24-hour IOP reduction.

OCT evaluation of neuroprotective effects of tafluprost on retinal injury after intravitreal injection of endothelin-1 in the rat eye.

PURPOSE: To determine whether optical coherence tomography (OCT) is a useful technique to monitor retinal damage and to evaluate the neuroprotective effect of topical tafluprost in a rat model of intravitreal endothelin-1 (ET-1) injection. METHODS: A single intravitreal injection of ET-1 (0.2-200 pmol/eye) was performed in one eye. Optical coherence tomography imaging was performed until 2 weeks after ET-1 injection. Subsequently, an intravitreal injection of ET-1 (20 pmol/eye) was performed in one eye of each rat, which was followed by topical instillation of tafluprost or saline once daily for 4 weeks. Optical coherence tomography imaging was performed until 4 weeks after ET-1 injection. After the last OCT session, retinal ganglion cells (RGCs) were retrogradely labeled with Fluorogold. RESULTS: Endothelin-1 at doses of 20 to 200 pmol/eye caused a significant decrease in inner retinal thickness, whereas ET-1 at doses of 0.2 to 5 pmol/eye did not. The inner retinal thickness at 2 weeks postinjection was strongly correlated with Fluorogold-labeled RGC counts in the central retina (r = 0.92, P < 0.001). The inner retina of eyes treated with tafluprost was significantly thicker than eyes treated with saline at 1 and 2 weeks (P = 0.038 and P = 0.045, respectively). Fluorogold-labeled RGC counts in the central retina of eyes treated with tafluprost were significantly greater than in eyes treated with saline (P = 0.03). CONCLUSIONS: Optical coherence tomography is useful for monitoring inner retinal damage in a rat model of intravitreal ET-1 injection. Daily topical administration of tafluprost may be protective against ET-1-induced retinal injury in the rat.

Ocular hypotensive effect of tafluprost in latanoprost low-responder cynomolgus monkeys.

PURPOSE: To determine the proportion of latanoprost low-responders among cynomolgus monkeys, and to evaluate the switching efficacy from latanoprost to tafluprost in latanoprost low-responder monkeys. METHODS: Thirty-nine ocular normotensive monkeys were used in this study. Latanoprost low-responders were detected using a 2-step evaluation procedure. In the first step, the response to single administration of latanoprost was investigated in all monkeys. In the second step, the response to 7-day administration of latanoprost was evaluated in screened monkeys. We defined latanoprost low-responders as any monkey that showed intraocular pressure (IOP) reduction of 1 mm Hg or less during the 7-day treatment. Switching efficacy from latanoprost to tafluprost was then evaluated in a 3-phase switching study. Latanoprost was topically administered for about 1 week in phases 1 and 3, with tafluprost being topically administered for about 1 week in phase 2. RESULTS: Eleven monkeys were "latanoprost low-responders." The maximal IOP reduction exhibited by these low-responders in the second step of the evaluation was 0.5±0.2 mm Hg (mean±SEM) during saline treatment and 0.8±0.2 mm Hg during latanoprost treatment. In the 3-phase switching study, the maximal IOP reductions were: 0.4±0.2 mm Hg in phase 1 (latanoprost), 2.4±0.3 mm Hg in phase 2 (tafluprost), and 0.5±0.2 mm Hg in phase 3 (latanoprost). CONCLUSIONS: Latanoprost low-responders exist among cynomolgus monkeys. Switching from latanoprost to tafluprost reduced IOP, and tafluprost's IOP-lowering effect disappeared after switching back to latanoprost in the latanoprost low-responder monkeys. These results suggested that tafluprost might be effective for latanoprost nonresponder patients.

Effects of prostaglandin F(2α) analogues on endothelin-1-induced impairment of rabbit ocular blood flow: comparison among tafluprost, travoprost, and latanoprost.

We investigated the effects of prostaglandin F(2α) (PGF(2α)) analogues on the endothelin-1 (ET-1)-induced impairment of optic nerve head (ONH) blood flow and on ET-1-induced contraction in isolated ciliary artery segments. In male rabbits, one of four PGF(2α) analogues [0.0015% tafluprost, 0.0015% 15-hydroxyl tafluprost (15-OH tafluprost), 0.005% latanoprost, or 0.004% travoprost] was topically administered at various pretreatment times before intravitreal ET-1 injection. ONH blood flow was estimated by the laser speckle method, which expresses blood velocity as a quantitative index, the squared blur rate (SBR). SBR was measured just before (baseline value) and at 30, 60, and 120 min after ET-1 injection. SBR was significantly decreased from 4.47 ± 0.20 to 3.50 ± 0.10 (78.6 ± 2.4% of baseline) at 120 min after intravitreal ET-1 injection (5 pmol/eye). The ET-1-induced decrease was almost completely prevented by tafluprost and significantly inhibited by the other three analogues. The inhibitory effect lasted longest with tafluprost, as indicated by the effective pretreatment times (tafluprost: 90, 120, or 240 min; 15-OH tafluprost: 90, but not 120 or 240 min; latanoprost and travoprost: 120, but not 240 min). In vitro, the effects of PGF(2α) analogues on ET-1-induced contractions in male rabbit ciliary arteries were evaluated using an isometric tension recording system. Tafluprost, latanoprost, travoprost, and 15-OH tafluprost concentration-dependently relaxed the 10 nM ET-1-induced ciliary artery contraction. Improvement of the ocular circulation may be superior with tafluprost than with the other PGF(2α) analogues. The underlying mechanism may involve relaxation of ocular resistance vessels.

Effects of repeated administrations of tafluprost, latanoprost, and travoprost on optic nerve head blood flow in conscious normal rabbits.

PURPOSE: The aim of this study was to evaluate and compare the effects of repeated administrations of three prostaglandin F(2alpha) analogs (tafluprost, latanoprost, and travoprost) on optic nerve head (ONH) blood flow in normal rabbits. METHODS: Male Dutch rabbits were housed under a 12-h light-dark cycle for use in this study. A quantitative index of blood flow, the squared blur rate (SBR), was determined using laser speckle flowgraphy. Saline, 0.0015% tafluprost, 0.005% latanoprost, or 0.004% travoprost (each 50 microL) was topically administered into the left eye once daily for 28 days. ONH blood flow was measured before the start at the course of treatment (baseline), and on day 14 and/or day 28 [measurements being made at 0, 30, and/or 60 min after drugs application on day 14 and/or day 28]. Heart rate was also measured at these time points. RESULTS: Tafluprost, latanoprost, and travoprost each increased the ONH blood flow at all measurement points on day 14 and/or day 28. The 0 min SBR value on day 14 was greater than the baseline SBR value by 8.7% + or - 4.4% for tafluprost and by 5.8% + or - 1.7% for latanoprost. The 0 min SBR value on day 28 was greater than the baseline SBR value by 11.9% + or - 3.9% for tafluprost, by 7.2% + or - 4.3% for latanoprost, and by 6.7% + or - 3.5% for travoprost. The increasing state of the ONH blood flow continued within 60 min after a topical administration of tafluprost, latanoprost, or travoprost. Tafluprost, latanoprost, and travoprost did not change heart rate (vs. the baseline value) at any measurement points. CONCLUSIONS: Repeated topical administration of any of the three prostaglandin F(2alpha) analogs increased ONH blood flow in rabbits, without changing heart rate. The increase in ONH blood flow induced by tafluprost was greater than that induced by latanoprost (P = 0.086) or travoprost (P = 0.037) at 60 min on day 28.

Ocular hypotensive effects of anti-glaucoma agents in mice.

PURPOSE: To evaluate the ocular hypotensive effects induced by topical application of anti-glaucoma agents in mice. METHODS: Representative drugs (latanoprost and tafluprost [for prostanoid FP receptor agonists], timolol [for beta-adrenoceptor antagonists], dipivefrin [for alphabeta-adrenoceptor agonists], dorzolamide [for carbonic anhydrase inhibitors], pilocarpine [for muscarinic receptor agonists], bunazosin [for alpha(1)-adrenoceptor antagonists], or brimonidine [for alpha(2)-adrenoceptor agonists]) were used as anti-glaucoma agents; each one being topically applied once in a given male ddY mouse. Intraocular pressure (IOP) was measured using the microneedle method under general anesthesia. IOP was measured before, and at 1, 2, 3, and 4 h after administration of each drug. The contralateral eyes were untreated. At the each time point, the induced IOP reduction was evaluated by calculating the difference in IOP between the treated and untreated eyes in one and the same mouse. RESULTS: All of the evaluated anti-glaucoma agents reduced IOP in mice. The 2 prostanoid FP receptor agonists, the beta-adrenoceptor antagonist, and the alphabeta-adrenoceptor agonist began significantly to reduce IOP 2 h after their administration, and mostly induced a long-lasting IOP reduction. The alpha(1)-adrenoceptor antagonist, the alpha(2)-adrenoceptor agonist, the muscarinic receptor agonist, and the carbonic anhydrase inhibitor began reducing the IOP within 1 h after their administration, but their effects waned fairly quickly (the IOP reductions being lost by 3 h after their administration). Concomitant administration of timolol and tafluprost or of dorzolamide and tafluprost induced a significantly greater IOP reduction than that induced by either of the individual components. CONCLUSIONS: In this study, all the anti-glaucoma agents tested had apparent ocular hypotensive effects in mice. Our data suggest that the mouse may be a useful animal for the evaluation of the pharmacological effects of agents with various anti-glaucoma mechanisms, and for the evaluation of the enhanced ocular hypotensive effects that may be induced by the concomitant use of 2 anti-glaucoma agents.

Prostanoids in the therapy of glaucoma.

Elevated intraocular pressure (IOP) is one of the most important risk factors for the development of glaucoma, which is a progressive optic neuropathy. Lowering IOP is currently the only therapeutic approach to the therapy of glaucoma. Since the use of pilocarpine eye drops for glaucoma treatment was reported in the late 1870s, academic researchers and pharmaceutical companies attempted to discover new drugs with more potent, prolonged, and safer IOP-reducing effects. These persistent efforts finally paid off, and prostanoids with FP-receptor agonist activity were found to be very potent IOP-lowering agents. To date, three prostanoids (latanoprost, travoprost and bimatoprost) have been launched in many countries, and now a new FP-receptor agonist, tafluprost, is entering clinical development. All of these prostanoids are superior to the beta-adrenoceptor antagonists in their IOP-lowering efficacy, and no severe side effects have been reported in their long-term clinical use. In addition, tafluprost may be expected to improve ocular blood flow. Hence, prostanoids currently occupy center stage among glaucoma medications. It cannot be denied that in terms of efficacy, safety, patient compliance, and medical economy prostanoids are currently the first-line medicines among ocular antihypertensive drugs.

Intravitreal injection of endothelin-1 caused optic nerve damage following to ocular hypoperfusion in rabbits.

The purpose of this study was to investigate the time course of the ocular hypoperfusion, retinal damage, and optic nerve damage induced by intravitreal injection of endothelin-1 (ET-1) in rabbits. ET-1, at 5 pmol (20 microL, twice a week for 2 or 4 weeks), was injected from the pars plana into the posterior vitreous of the right eye. Optic nerve head (ONH) blood flow and retinal artery diameter, together with the neurofilament light chain (NF-L) content, retinal morphology, and axon density of the optic nerve, were evaluated at 2, 4, and 8 weeks after the first injection of ET-1 (n=7 or 8). Tissue blood velocity in ONH was measured using a laser speckle method, and the diameter of major retinal arteries on the rim of the ONH was calculated from fundus photographs by a masked observer. Histological analysis and immunoblot evaluation of NF-L in the optic nerve were performed to evaluate optic nerve damage. At 2 weeks after the first ET-1 injection, tissue blood velocity was decreased by approximately 20% (versus the contralateral eye), and the diameter of retinal arteries had decreased by approximately 40%. These changes were sustained at the same level until 8 weeks after the first ET-1 injection. At 4 and 8 weeks after the first ET-1 injection, the amount of NF-L in the optic nerve was significantly less in the ET-1 treated eyes than in the contralateral eyes. At 8 weeks after the first ET-1 injection, a loss of myelinated axons and increases in gliosis and connective tissue were noted in the optic nerve of the treated eye, and the optic nerve-axon number had decreased significantly (each, versus the untreated eye). Retinal ganglion cells in the retina were not observed any damage at 2, 4, and 8 weeks after ET-1 injection. In conclusion, intravitreal injection of ET-1 induced chronic hypoperfusion in the ONH and retina, which presumably caused decreases in NF-L content and axon number in the optic nerve noted in the later part of the observation period.

Continuous monitoring of circadian variations in intraocular pressure by telemetry system throughout a 12-week treatment with timolol maleate in rabbits.

AIM: The aim of this study was to examine the effect of a 12-week treatment with two formulations of timolol maleate on the amplitude of the circadian fluctuation in intraocular pressure (IOP). METHODS: Conscious Japanese White rabbits housed under a controlled 12-hour light-dark cycle were used. IOP was measured by a telemetry system. Each animal was treated topically for 12 weeks with 0.5% timolol solution (TM) twice-daily, 0.5% timolol gel-forming solution (TM-gel) once-daily, or saline twice-daily, and the circadian variation in IOP was measured every week. RESULTS: Administration of TM or TM-gel did not change IOP in the light phase, but significantly reduced it in the dark phase in each of the 12 weeks. The IOP reductions at 2 h after administration in the TM and TM-gel groups over the 12 weeks were, respectively, 3.6 +/- 0.3 mmHg and 3.4 +/- 0.2 mmHg versus the Saline group. The amplitudes of the circadian fluctuations in IOP in the TM group in weeks 3, 6, and 12 were 15%, 15%, and 18% smaller than those in the Saline group, while the corresponding values for the TM-gel group were 18%, 16%, and 19%, respectively. CONCLUSIONS: TM-gel administered once-daily was as effective at lowering IOP as TM administrated twice-daily over the 12-week experimental period. This study reveals that, in rabbits, both formulations of the timolol maleate induced significant IOP reductions in the dark phase and decreased the amplitudes of the circadian fluctuations in IOP for 12 successive weeks.

Effects of bunazosin hydrochloride on ciliary muscle constriction and matrix metalloproteinase activities.

PURPOSE: To clarify the mechanism by which bunazosin hydrochloride (BZ), a selective alpha1-adrenoceptor antagonist, increases uveoscleral outflow. METHODS: The effects of BZ on matrix metalloproteinase (MMP) activities in cultured monkey ciliary muscle cells, and on phenylephrine hydrochloride-induced constriction in bovine ciliary muscles, were examined. Also, the possible additive ocular hypotensive effects of BZ and latanoprost (LP) were evaluated in ocular normotensive monkeys. RESULTS: Although BZ at 10 to 10 M did not increase MMP-2, -3, and -9 activities in the culture medium of ciliary muscle cells, BZ at 10 to 10 M inhibited phenylephrine hydrochloride-induced constriction in ciliary muscles. The maximal reduction in intraocular pressure of concomitant administration of BZ and LP was greater than that of BZ alone and tended to be greater than that of LP alone. CONCLUSION: These findings, in normotensive monkeys, indicate that the mechanism whereby BZ increases uveoscleral outflow is independent of an effect on MMPs and is partly due to relaxation of the ciliary muscle. This effect is different from that of LP, which might help to explain the finding that topical concomitant administration of BZ and LP increased AUC(0-6h) value (IOP reduction) to 201% and 145% of BZ and LP given alone, respectively.

Abnormal protein profiles in tears with dry eye syndrome.

PURPOSE: To verify the hypothesis that protein concentrations, such as lactoferrin, epidermal growth factor (EGF), and aquaporin 5 (AQP5), in tears are abnormal in patients with dry eye. DESIGN: Prospective case-control study. METHODS: One hundred three dry eye patients were divided into three groups: dry eye not associated with the Sjögren syndrome (non-SS; n = 71), Sjögren syndrome (SS; n = 23), and Stevens-Johnson syndrome (SJS; n = 9). Sixteen normal control subjects were also checked. The concentrations of lactoerrin, EGF, and AQP5 were measured by enzyme-linked immunosorbent assay. RESULTS: The concentration of lactoferrin was significantly decreased in tears of non-SS (P =.0001), SS (P =.00005), and SJS (P =.0006) patients compared with control subjects. The concentration of EGF was significantly decreased in non-SS (P =.0005), SS (P =.00002), and SJS (P =.0001) patients compared with control subjects. The concentration of AQP5 was significantly increased in tears of only SS patients (P =.01) compared with control subjects and increased in tears of only SS patients compared with non-SS patients (P =.007). CONCLUSIONS: The decrease in both lactoferrin and EGF was found not only in SS patients but also in non-SS patients, indicating that tear components in dry eyes differ in their quantity and quality. Quantification of AQP5 increased only in SS patients, suggesting that AQP5 protein leaks into the tears when acinar cells of the lacrimal gland are damaged by lymphocytic infiltration.