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WO1999007353A1 - UTILISATION D'ANTAGONISTES DE RECEPTEUR α1A-ADRENERGIQUE DANS LA THERAPIE DU GLAUCOME - Google Patents

UTILISATION D'ANTAGONISTES DE RECEPTEUR α1A-ADRENERGIQUE DANS LA THERAPIE DU GLAUCOME Download PDF

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WO1999007353A1
WO1999007353A1 PCT/US1998/015652 US9815652W WO9907353A1 WO 1999007353 A1 WO1999007353 A1 WO 1999007353A1 US 9815652 W US9815652 W US 9815652W WO 9907353 A1 WO9907353 A1 WO 9907353A1
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adrenergic receptor
compound
iop
receptor
intraocular pressure
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PCT/US1998/015652
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English (en)
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Steven M. Podos
Thomas W. Mittag
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The Mount Sinai School Of Medicine Of The City University Of New York
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/94—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving narcotics or drugs or pharmaceuticals, neurotransmitters or associated receptors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value

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  • the present invention relates to the use of agents which act as specific antagonists of the ⁇ l A adrenergic receptor to decrease intraocular pressure in subjects in need of such treatment, for example, in patients suffering from glaucoma, and for methods of identifying compounds which may be useful in decreasing intraocular pressure.
  • Glaucoma is a major eye disease which can cause progressive loss of vision leading to blindness.
  • the majority of human glaucomas are associated with increased intraocular pressure ("IOP").
  • IOP intraocular pressure
  • High IOP is considered the major risk factor for glaucomatous visual impairment resulting from death of retinal ganglion cells, loss of the nerve fiber layer in the retina, and the destruction of the axons in the optic nerve.
  • Current treatments are aimed at reducing IOP.
  • Drugs which act primarily by decreasing the formation of aqueous humor (“AH") within the eye include beta- adrenergic blockers (e.g., timolol), topical carbonic anhydrase inhibitors (e.g., dorzolamide) and alpha-2-adrenergic receptor agonists (e.g., clonidine derivatives).
  • AH aqueous humor
  • a drug which lowers IOP by increasing the outflow of AH via the uveoscleral route is represented by the prostaglandin derivative latanoprost.
  • the third mechanism for lowering IOP is to decrease the resistance to AH outflow in the trabecular meshwork outflow channels.
  • Pilocarpine and epinephrine act primarily by this mechanism. These older agents have been gradually replaced over recent years by alternative drugs acting by other mechanisms which have greater efficacy and fewer ocular side effects. It is generally considered that the ideal ocular hypotensive agent for treating glaucoma would act by a trabecular mechanism, at the site of the primary pathology in most open angle glaucomas.
  • the present invention relates to the use of adrenergic antagonist compounds with specificity for the ⁇ l A adrenergic receptor subtype for decreasing IOP. It is based, at least in part, on the discovery that selective ⁇ l A adrenergic receptor antagonists such as 5-methylurapidil (“5-MU”) and WB 4101 hydrochloride increase outflow facility of aqueous humor and decrease IOP in a primate model of human glaucoma.
  • 5-MU 5-methylurapidil
  • WB 4101 hydrochloride increase outflow facility of aqueous humor and decrease IOP in a primate model of human glaucoma.
  • 5-MU 5- methylurapidil
  • ⁇ l-blockers have low subtype selectivity acting at more than one of these receptors. It is likely that the variability of responses and side effects observed with ⁇ l -antagonists such as prazosin, thymoxamine or corynanthine is due to their lack of specificity for the different subtypes of ⁇ l -adrenergic receptors.
  • agents which act as antagonists with specificity for the ⁇ lA-adrenergic receptor and particularly agents which have a greater than 20-fold greater affinity for binding at the ⁇ lA receptor relative to the ⁇ IB and/or ⁇ lC receptors, including but not limited to 5-MU and WB-4101 and compounds which compete with 5-MU or WB 4101 for binding at the ⁇ l A receptor with the required specificity, may be used as ocular hypotensive agents.
  • FIGURE 1 Effects of a single dose of 1 % (open circles) or 2% (closed circles) 5-mefhylurapidil on intraocular pressure (IOP) in 8 normal monkeys. Points represent mean change in IOP from baseline values and the limits ⁇ SEM change. Asterisks indicate statistically significant reductions in IOP compared with baseline values (two-tailed paired t test, p ⁇ 0.05).
  • FIGURE 2 Effects of a single dose of 1% (open circles) or 2% (closed circles) 5-mefhylurapidil on pupillary diameter (PD) in 8 normal monkeys. Points represent mean change in PD from baseline values and the limits ⁇ SEM change. Asterisks indicate statistcally significant reductions in PD compared with baseline values (two-tailed paired t test, p ⁇ 0.05).
  • FIGURE 3 Effects of a single dose of 1% (open circles) or 2% (closed circles) 5-methylurapidil on intraocular pressure (IOP) in 8 unilaterally glaucomatous monkeys. Points represent mean change in IOP from baseline values and the limits ⁇ SEM change. Asterisk indicates statistically significant reduction in IOP compared with the baseline day values (two-tailed paired t test, p ⁇ 0.05).
  • FIGURE 4 Effects of twice-daily administration of 2% 5- methylurapidil to eyes with glaucoma of 7 unilaterally glaucomatous monkeys for 5 days. Points represent mean values of IOP on vehicle-treated day (open circles), day 1 (closed circles), day 3 (open squares), and day 5 (closed squares) of treatment and bars indicate ⁇ SEM. Asterisks indicate statistically significant reductions in intraocular pressure (IOP) compared with vehicle-treated values (two-tailed paired t test, p ⁇ 0.05).
  • IOP intraocular pressure
  • FIGURE 5 Effects on IOP of the contralateral non-glaucomatoous eyes of twice-daily administration of 2% 5-MU for 5 successive days to the eyes with glaucoma in 7 unilateral glaucomatous monkeys.
  • Points represent means of IOP on vehicle-treated day (open circles), day 1 (closed circles) and day 5 (closed squares) of treatment and bars indicate ⁇ SEM.
  • Asterisks indicate statistically significant reductions in intraocular pressure (IOP) compared with vehicle-treated values (two- tailed Bonferroni t-test, ⁇ 0.05).
  • the present invention relates to a method for decreasing intraocular pressure in a subject in need of such treatment (including, but not limited to, a subject suffering from glaucoma), comprising administering, to the subject, an effective amount of a selective ⁇ lA adrenergic receptor antagonist.
  • the selective antagonist has an affinity for binding to the ⁇ l A adrenergic receptor which is at least 20 times greater than the affinity for the antagonist to bind to the ⁇ lB or the ⁇ lC adrenergic receptors, using measurements as described in (Minneman and Esbenshade, 1994, Annu. Rev. Pharmacol. Toxicol.
  • selective antagonists include 5- methylurapidil, having the following chemical structure (I), and WB-4101 hydrochloride, having the following chemical structure (II):
  • WB-4101 hydrochloride as well as agents which compete with either 5-methylurapidil or WB-4101 hydrochloride (and structurally related compounds) for binding with the ⁇ l A adrenergic receptor and/or are selective in binding to that receptor.
  • the present invention also provides for a method for the identification of a compound which may be useful in decreasing intraocular pressure in a subject in need of such treatment, comprising (i) determining whether the compound acts as an antagonist at the ⁇ l adrenergic receptor and (ii) measuring the affinity of the compound for binding to the ⁇ l A adrenergic receptor, the ⁇ IB adrenergic receptor, and the ⁇ lC adrenergic receptor, wherein the ability of the compound to act as an antagonist at the ⁇ l adrenergic receptor and to selectively bind to the ⁇ l A receptor has a positive correlation with the ability of the compound to be effective in decreasing intraocular pressure, ⁇ l adrenergic receptor antagonist action is defined herein as the ability of a compound to inhibit effects mediated by the ⁇ l adrenergic receptor, such effects including, but not limited to, a hypertensive effect (wherein antagonism results in a hypotensive effect), a positive inotropic
  • ⁇ l A adrenergic receptors may be measured as follows.
  • the cellular effect of activation of ⁇ l receptors is mobilization of Ca 2+ via Ca 2+ channels or release from intracellular stores.
  • the Ca 2+ mobilization can be determined for each subtype by Ca 2+ -sensitive fluorescent dyes.
  • Ca 2+ mobilization by ⁇ l A or ⁇ lB receptors may be measured by contraction of smooth muscle or another physiological response, such as the inotropic response.
  • selective antagonism of ⁇ lA receptors by a drug may be determined, for example, by comparison with a known selective agent such as chloroethyl clonidine ("CEC"), an irreversible blocker.
  • CEC chloroethyl clonidine
  • ⁇ lA selectivity can be determined by competition against prazosin (which non-selectively binds to all l receptor subtypes) and comparing with CEC, WB-4101 and 5-MU, the last two of which are known to be ⁇ l A receptor selective.
  • the preferred method is to use cell lines which express the specific subtypes as a preliminary selection method, and then to determine the specificity of a test antagonist by measuring its IC50 in blocking norepinephrine-induced Ca 2+ mobilization.
  • Such a method may be used to screen a plurality of test compounds in order to identify a compound useful in decreasing intraocular pressure.
  • selective binding is preferably manifested as an at least 20-fold greater affinity for the ⁇ l A adrenergic receptor relative to the ⁇ lB or ⁇ lC/D adrenergic receptors.
  • such a compound competes with 5-MU or WB-4101 (but is distinct from 5-MU or WB-4101) for selectively binding to the ⁇ l A adrenergic receptor.
  • the present invention provides a method for identifying compounds which would more likely be clinically useful.
  • the present invention further provides for a method of decreasing intraocular pressure in a subject in need of such treatment comprising administering, to the subject, an effective amount of a compound identified by the foregoing method.
  • the administration of such an antagonist may become more effective with repeated dosing, as tachyphylaxis was not observed with repeat 5-MU administration; rather, the effectiveness was observed to increase.
  • the present invention is illustrated by the following nonlimiting working examples, which demonstrate that (i) the selective ⁇ lA adrenergic receptor antagonists 5-MU and WB-4101 decrease IOP and increase outflow facility of AH in normal and glaucomatous monkey eyes; (ii) the activity of 5-MU in decreasing IOP does not derive from its 5HT 1A agonist activity; and (iii) 5-MU selectively acts as an antagonist at the l A-adrenergic receptor.
  • IOP On each day of the study IOP was measured with a calibrated pneumotonometer (model classic, Mentor, Norwell, MA) at 0 hr (prior to drug administration), 0.5 hour and then hourly until 6 hours after drug administration.
  • the pupil diameter (PD) was measured with a millimeter ruler under normal room light at the same time and same intervals as IOP measurements in normal monkeys. Slit-lamp examinations were performed at 0 hour (pre-treatment) and 1, 3 and 5 hours (post- treatment) for detection of corneal changes and aqueous humor flare or cells, using maximum magnification in a dark room.
  • Aqueous humor flow measurements were performed using a scanning computerized fluorophotometer and a software analysis package (Coherent Fluorotron, Coherent, Palo Alto, CA) .
  • Fluorescein was iontophoresed into the central corneas of both eyes (with an electrode of 10% fluorescein in 2% agar gel) for 7 minutes at 4:00 p.m. on the day prior to aqueous flow measurements.
  • Baseline aqueous humor flow rates were taken at 1 hour intervals for 4 hours beginning at 9:30 a.m. The following day, flow measurements were repeated, as done on the baseline day, beginning 1 hour after drug application.
  • the washout period between each test on the same animal was at least one week.
  • Uveoscleral outflow was determined with a perfusion technique using fluorescein isothiocyanate-dextran beginning 1 hour after 50 ⁇ l of topical 2% 5-MU in 8 rabbits. Naive albino rabbits weighing 2-3 kg were used. The rabbits were restrained in cloth wrappers for all measurements. The care and use of animals conformed to the Declaration of Helsinki and The Guiding Principles in the Care and Use of Animals (DHEW Publication, NIH 86-23). Baseline IOPs were measured at 9:00 a.m. with a calibrated pneumatonometer following topical application of one drop of proparacaine hydrochloride 0.5%.
  • the rabbits were anesthetized with intravenous urethane 40% (Sigma Chemical CO., St. Louis, MO, initial dose 0.8g/kg body weight, additional doses given when required).
  • intravenous urethane 40% Sigma Chemical CO., St. Louis, MO, initial dose 0.8g/kg body weight, additional doses given when required.
  • the head was then held securely in place with a head holder.
  • One drop of proparacaine 0.5% was applied to the cornea and two 23-gauge needles were inserted through the peripheral cornea into the anterior chamber in each eye. Needle A was attached to polyethylene tubing and a 5 ml infusion syringe filled with 10 "4 M fluorescein isothiocyanate-dextran (FITC- dextran) (71,200 MW, Sigma Chemical CO., St.
  • Needle B was attached to polyethylene tubing leading to a 5 ml withdrawl syringe or a buret through a two-way stopcock.
  • the syringes were controlled by an infusion/withdrawal pump (Model 944, Harvard Apparatus, South Natick, MA).
  • 1ml of 10 "4 M FITC-dextran was used to flush the anterior chamber at a rate of 0.5 ml/min for 2 min using both of syringes.
  • the syringe from needle B was then disconnected and the buret was connected to the anterior chamber using the stopcock.
  • the FITC-dextran solution was infused into the anterior chamber using syringe A until the solution in the buret was 20 cm above the anterior chamber to establish an IOP of 15 mmHg.
  • the syringe B was then re-connected and the buret was disconnected from the anterior chamber.
  • the eye was continuously perfused with the FITC-dextran solution from syringe A to syringe B at the rate of 10 ul/min for 30 minutes.
  • the anterior chamber was then washed thoroughly with 2ml of PBS at a rate of 0.5 ml/min for 4 minutes. It was assumed that fluorescein tracer labeled fluid in the conventional outflow paths had been washed out.
  • the animal was killed by an overdose of intravenous urethane, the needles withdrawn, and the eye enucleated. The cornea was then removed and the eye was washed thoroughly with PBS. After the lens was discarded, the eye was dissected into uvea, fluid of posterior segment plus vitreous, and sclera. The sclera was minced with scissors. All samples were homogenized in 5-7 ml of PBS and centrifuged for 30 min. After centrifugation , the volume of each sample was measured and the supernatant was measured for the concentration of the FITC-dextran by using a fluorophotometer (Coherent Fluorotron Master, Palo Alto,CA). Forty-two different concentration of FITC-dextran were measured to construct a standard curve by computer.
  • a fluorophotometer Coherent Fluorotron Master, Palo Alto,CA
  • Uveoscleral outflow was considered to be the volume (Vu) of labeled anterior chamber fluid required to have deposited the amount of tracer recovered from the ocular tissues, divided by the duration (T) of the labeled infusion.
  • T duration
  • ng quantity of tracer in tissue or fluid
  • T Time of anterior chamber perfusion
  • FIGURE 3 Mucous discharge of the conjunctiva was observed in 1 of the 8 eyes treated with the 2% dose. The corneas of all animals remained clear.
  • the ocular hypotensive effect was observed to increase with successive dosing in a 5-day twice-daily administration of 2% 5-MU study (FIGURES 4 and 5).
  • the reduction in IOP became more pronounced at each interval from day 1 to day 5.
  • the maximum reduction in IOP (the differences in IOP between drug - treated and vehicle - treated values) at 1 hour after application was 6.9 ⁇ 1.3mmHg on day 1 and 15.1 ⁇ 2.9mmHg on day 5, (p ⁇ 0.05).
  • Mild corneal edema was observed in one of seven drug-treated eyes on day 4, but was not noted in any of the eyes on the day 5 examination.
  • t Values are mean ⁇ SEM. Intraocular pressure was measured with an electronic tonography apparatus.
  • t Values are mean ⁇ SEM. Blood pressure was measured with a sphingomanometer for newborns.
  • Some ⁇ ,-adrenergic antagonist drugs produce miosis and a reduction of intraocular pressure in animals and humans.
  • Thymoxamine a selective ⁇ r adrenergic antagonist
  • produces miosis without lowering IOP in normal human eyes Wand and Grant, 1976, Invest. Ohpthalmol. 15:400-403; Wand and Grant, 1980, Surg. Ophthalmol. 25:75-84.
  • prazosin which is also a selective ⁇ r adrenergic antagonist, has little pupillary effect, but can significantly lower IOP in animals (Rowland and Potter, 1980, Eur.J. Pharmacol. 64:361-363; Smith et al., 1989, Arch. Ophthalmol.
  • Corynanthine another ⁇ ,-adrenergic antagonist, reduces IOP but tachyphylaxis develops in humans (Serle et al., 1985, Ophthalmol. 92:977-980) and animals (Serle et al., 1984, Arch. Ophthalmol. 102:1385-1388).
  • the differences in response among various ⁇ , -blocking drugs could be due to differences in numbers and/or activities of ⁇ , -receptor subtypes at different sites or alternative signal transduction systems linked to the subtypes of ⁇ ,-adrenoceptors present in different tissues.
  • ⁇ ,-adrenergic receptor subtypes ⁇ 1A , ⁇ 1B , ⁇ lc D
  • 5-MU is one of the currently available drugs which has substantially different affinities for the pharmacologically defined ⁇ 1A and ⁇ 1B -subtypes.
  • 5-MU is also a potent agonist at the 5-HT 1A receptor (Hoyer et al., 1984, Pharmacol. Rev. 46: 157-203).
  • a population of 5- HT 1A receptors is present in the iris-ciliary body of the rabbit (Chidlow et al., 1995, Invest. Ophthalmol. Vis. Sci. 36:2238-2245) and human (Hoyer et al., 1984, Pharmacol. Rev. 46:157-203).
  • Ketanserinol which is a metabolite of ketanserin, is reported to have a greater ocular hypotensive effect than does ketanserin in normotensive rabbits (Espino and Musson, 1993, InvestOphthalmol. Vis. Sci. 34:1111).
  • 5- MU is a dual-action drug
  • its effect on aqueous humor dynamics could result from a combination of antagonism at ⁇ ,-receptors ( ⁇ 1A -subtype) and agonism at 5-HT receptors (5-HT 1A subytpe).
  • Some ⁇ - blockers used as ophthalmic drugs, such as carteolol, are dual - action drugs because they are ⁇ 2 - receptor antagonists, but have sympathomimetic activity at other types of adrenergic receptors.
  • This study on the effects of 5-MU on IOP and aqueous humor dynamics shows that 5-MU does reduce IOP bilaterally following unilateral administration in monkey eyes. The reduction in IOP appears to be dose-dependent.
  • the magnitude and the duration of IOP reduction is greater in the treated eyes than in contralateral fellow eyes, and greater in glaucomatous than in the normal monkey eyes.
  • the bilateral reduction in IOP may be caused by systemic transfer of drug, or mediation through the central nervous system, or through a non-adrenergic mechanism.
  • the drug produces miosis probably by inhibiting ⁇ , -receptor-mediated contraction of the dilator muscle of the iris.
  • the multiple-dose study in monkeys demonstrates an increase of the ocular hypotensive effect with repeated dosing, which differs from findings with another ⁇ ,-antagonist drug, corynanthine, where tachyphylaxis develops (Serle et al, 1985, Ophthalmol. 92:977-980).
  • Prazosin reduces IOP by reducing aqueous humor formation in animal eyes when administered topically (Krupin et al., 1980, Arch. Ophthalmol. 98:1639-1642).
  • Corynanthine reduces IOP without altering outflow facility or the rate of aqueous humor flow (Serle et al., 1984, Arch. Ophthalmol. 102:1385-1388).
  • 5-MU which combines antagonist activity at the ⁇ , A -adrenergic receptor subtype and agonist activity at the 5-HT 1A receptor subtype had effects on aqueous humor dynamics that are quite different from previously studied ⁇ , - receptor blockers.
  • Topical application of 5-MU to monkey eyes reduced IOP by increasing outflow facility up to 51% in the treated eye with a small, but significant increase in aqueous humor flow rate.
  • drug effects on uveoscleral outflow may be species-dependent, and could be different in the monkey eye.
  • the increase in outflow facility may relate to effects of 5-MU on trabecular tissue and to ⁇ -adrenoreceptor and 5-HT receptor systems in trabecular tissue or associated ciliary muscle.
  • Vascular mechanisms may also be involved in the ocular hypotensive responses to 5-MU.
  • Oral administration of the ⁇ , -receptor blocker prazosin reduces blood pressure.
  • the effect of this drug on aqueous humor production may be mediated in part by a decrease in systemic blood pressure
  • 5-MU also decreases blood pressure and heart rate by activation of a CNS 5-HT 1A -receptor system (Dreteler et al, 1990, Eur. J. Pharmacol. 180:339-349; Dreteler et al., 1981, J. Cardiovasc. Pharmacol. 17:488-493).
  • This drug may thus affect the tone of arterial or venous vessels that could influence ocular blood flow, aqueous formation and outflow facility.
  • 5-methylurapidil a newly recognized dual-action drug which is an ⁇ , A -adrenergic antagonist and a 5-HT, A agonist, reduced IOP and pupil size in normal and glaucomatous monkey eyes with few adverse effects.
  • drugs with the above receptor profile of activity can cause a reduction in IOP in primates by increasing outflow facility and that multiple dosing does not result in tachyplylaxis but causes a cumulative increase in response.
  • Intraocular Pressure (mean mmHg ⁇ SEM) at time (hrs) pre- and post- treatment
  • a 50 ⁇ l dose of 0.15%> p-MPPI was applied to one eye of six normal monkeys. IOP and pupil size were measured before treatment and then hourly for six hours after dosing. After a two week washout period, 50 ⁇ l of 0.2%) p-MPPI was randomly applied to one eye of six normal monkeys, and the same volume of saline was applied to the fellow control eye. One hour after the p-MPPI or saline dosing, 50 ⁇ l of 2% 5-MU was applied to both eyes of all six monkeys. IOP was measured prior to the p-MPPI pre-treatment, prior to the 5- MU dosing, and then hourly up to six hours after 5-MU treatment.
  • the present invention therefore provides for the use of effective concentrations of WB4101 and/or a salt thereof, including, but not limited to, WB4101 hydrochloride, in methods of decreasing intraocular, in particular in the treatment of glaucoma.

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Abstract

Identification et utilisation d'agents qui ont une action en tant qu'antagonistes sélectifs du récepteur α1A-adrénergique pour faire diminuer la pression intraoculaire.
PCT/US1998/015652 1997-08-05 1998-07-29 UTILISATION D'ANTAGONISTES DE RECEPTEUR α1A-ADRENERGIQUE DANS LA THERAPIE DU GLAUCOME WO1999007353A1 (fr)

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Cited By (4)

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US6469065B1 (en) 1996-02-02 2002-10-22 Nitromed, Inc. Nitrosated and nitrosylated α-adrenergic receptor antagonist, compositions and methods of use
US10993932B2 (en) 2018-10-26 2021-05-04 Ocuphire Pharma, Inc. Methods and compositions for treatment of presbyopia, mydriasis, and other ocular disorders
US11566005B2 (en) 2021-05-18 2023-01-31 Ocuphire Pharma, Inc. Highly pure phentolamine mesylate and methods for making same
US12161629B2 (en) 2018-10-15 2024-12-10 Opus Genetics, Inc. Methods and compositions for treatment of glaucoma and related conditions

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US5086074A (en) * 1988-01-15 1992-02-04 Abbott Laboratories 1-aminomethyl-1,2,3,4-tetrahydronaphthalenes
WO1993004686A1 (fr) * 1991-09-12 1993-03-18 Smithkline Beecham Corporation Composes chimiques
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6469065B1 (en) 1996-02-02 2002-10-22 Nitromed, Inc. Nitrosated and nitrosylated α-adrenergic receptor antagonist, compositions and methods of use
US12161629B2 (en) 2018-10-15 2024-12-10 Opus Genetics, Inc. Methods and compositions for treatment of glaucoma and related conditions
US10993932B2 (en) 2018-10-26 2021-05-04 Ocuphire Pharma, Inc. Methods and compositions for treatment of presbyopia, mydriasis, and other ocular disorders
US11400077B2 (en) 2018-10-26 2022-08-02 Ocuphire Pharma, Inc. Methods and compositions for treatment of presbyopia, mydriasis, and other ocular disorders
US12016841B2 (en) 2018-10-26 2024-06-25 Ocuphire Pharma, Inc. Methods and compositions for treatment of presbyopia, mydriasis, and other ocular disorders
US12201616B2 (en) 2018-10-26 2025-01-21 Opus Genetics, Inc. Methods and compositions for treatment of mydriasis
US12201615B2 (en) 2018-10-26 2025-01-21 Opus Genetics, Inc. Methods and compositions for treatment of mydriasis
US11566005B2 (en) 2021-05-18 2023-01-31 Ocuphire Pharma, Inc. Highly pure phentolamine mesylate and methods for making same
US11976044B2 (en) 2021-05-18 2024-05-07 Ocuphire Pharma, Inc. Highly pure phentolamine mesylate

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