WO1987007141A1 - Methode de traitement du glaucome - Google Patents

Methode de traitement du glaucome Download PDF

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Publication number
WO1987007141A1
WO1987007141A1 PCT/US1986/001862 US8601862W WO8707141A1 WO 1987007141 A1 WO1987007141 A1 WO 1987007141A1 US 8601862 W US8601862 W US 8601862W WO 8707141 A1 WO8707141 A1 WO 8707141A1
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WIPO (PCT)
Prior art keywords
epinephrine
dexamethasone
corticosteroid
solution
adrenergic agent
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Application number
PCT/US1986/001862
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English (en)
Inventor
Bernard Schwartz
Original Assignee
New England Medical Center Hospitals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by New England Medical Center Hospitals, Inc. filed Critical New England Medical Center Hospitals, Inc.
Publication of WO1987007141A1 publication Critical patent/WO1987007141A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone

Definitions

  • Glaucoma is a disease of the eye characterized by increased intraocular pressure. The most common cause of glaucoma is restricted outflow of aqueous fluid from the anterior chamber of the eye through Schlemm's canal, the trabecular meshw ⁇ rk and the aqueous veins, shown in the diagram of the human eye in Fig. 1. Glaucoma, if untreated, can cause excavation and degeneration of the optic disc and nerve fiber bundle damage producing defects in the field of vision and eventually permanent blindness. Roughly two million Americans are afflicted, making glaucoma one of the leading causes of blindness in the " United States.
  • Glaucoma may have a variety of causes, including hereditary predisposition, congenital malformation, disease, injury or adverse drug reaction.
  • angle-closure glaucoma occurs because the outflow of the aqueous humor is mechanically prevented by contact of the iris with the trabecular drainage meshwork and peripheral cornea.
  • Capsular glaucoma occurs in association with the widespread deposition of degenerative substance on the lens capsule, ocular blood vessels, iris and ciliary body.
  • Corticosteroid-induced glaucoma is due to a heritary predisposition to increased intraocular pressure after local instillation of corticosteroid-containing eyedrops.
  • glaucoma Other types include hypersecretion glaucoma due to the excessive formation of aqueous humor; malignant glaucoma due to forward displacement of the iris and lens, obliterating the anterior chamber; and open-angle glaucoma, in which the aqueous humor has free access to the trabecular meshwork.
  • Glaucoma is treated either surgically or with antiglaucomatous agents.
  • antiglaucomatous agents include echothiophate iodide, pilocarpine, methazolamide, timolol, and epinephrine, dipivalyl epinephrine and other epinephrine salts.
  • Echothiophate iodide is a long-acting cholinesterase inhibitor for topical use which enhances the effect of endogenously-liberated acetylcholine in parasympathetically innervated structures of the eye to increase outflow of the aqueous humor to decrease intraocular pressure.
  • Pilocarpine is a topically applied alkaloid which acts as a parasympathomimetic agent.
  • Methazolamide is a potent inhibitor of the enzyme carbonic anahydrase which is taken orally and acts to lower intraocular pressure by inhibiting carbonic anhydrase in the various tissues of the eye.
  • Timolol maleate is a general beta-adrenergic receptor-blocking agent which is effective in decreasing intraocular pressure.
  • Epinephrine bi ar ate (-)-3,4,-Dihydroxy-alpha-[(me hylamino) methyl] benzyl alcohol (+) tartrate (1:1) salt, is an adrenergic agent which reduces intraocular pressure by reducing the rate of aqueous formation and increasing the outflow of aqueous humor from the eye.
  • Epinephrine is a very effective drug against glaucoma and deserves use as the initial medical treatment of mild cases as well as in addition to other medications when required for control of difficult cases.
  • Clinical studies, reported in Ocular Pharmacology, at pages 275-290 by William H. Havener (The C.V. Mosby Co., St. Louis, 1983), of a number of sympathomimetic compounds showed that a 1% to 2% solution of levo-epinephrine often helps to control glaucoma.
  • epinephrine frequently causes side effects such as local allergy and systemic cardiovascular adrenergic , responses and it may cause angle-closure glaucoma and aphakic maculopathy.
  • a pressure-lowering effect can be demonstrated with epinephrine concentrations as low as 0.125%. However, a substantially greater response occurs with a 1% to 2% solution.
  • Dipivalyl epinephrine is a lipophilic epinephrine derivative and is converted to epinephrine in the ocular tissue. It is reported to have fewer side effect than epinephrine (William H. Havener, Ocular Pharmacology at pages 287-289)
  • steroids are not used in the treatment of glaucoma. Rather, prolonged use of steroids such as dexamethasone sodium phosphate can result in elevated intraocular pressure, damage to the optic nerve, defects in visual acuity and fields of vision, posterior subcapsular cataract formation or secondary ocular infections. Further, viral, bacterial and fungal infections of the cornea may be exacerbated by the topical application of steroids to the eye.
  • antiglaucomatous agents are generally effective in the treatment of glaucoma, they have both systemic and local side effects which may be serious in combination with other medical treatments such as anesthesia or the systemic use of other drugs.
  • Beta blocker drugs such as timolol, betaxalol and levobunolol cannot be used with people suffering from asthma or heart problems.
  • Systemic effects of epinephrine include increased blood pressure, faintness, headaches, and interactions with anesthesia.
  • the side effects of topical epinephrine include burning, slow wound healing, pigment deposition and eyelash loss.
  • Corneal pigmentation caused by epinephrine is particularly likely to occur in eyes with a damaged epithelium and is enhanced by the use of old and discolored solutions of oxidized epinephrine.
  • Topical epinephrine therapy can also cause plastic artificial eyes and contact lenses to turn black.
  • the present invention is a method for treating glaucoma in humans which consists of topically applying to the eye two drugs: a corticosteroid and an adrenergic agent, including alpha and beta agonists and antagonists.
  • the preferred drugs are dexamethasone and epinephrine or dipivalyl epinephrine. The treatment results in a decrease in intraocular pressure.
  • a solution of less than 0.1% dexamethasone is topically applied to the eye followed by topical application of a solution of less than 2% epinephrine or 0.1% dipivalyl epinephrine.
  • concentrations of 0.1% or more prolonged use of dexamethasone can produce increased intraocular pressure.
  • the interaction of the two drugs is important in determining the extent and duration of decrease of intraocular pressure, as shown by dose response curves relating intraocular pressure to the concentrations of the dexamethasone and epinephrine.
  • the two drugs may be topically applied in combination or in sequence.
  • the corticosteroid may also be given orally although this is not the preferred route of administration.
  • Fig. 1 is a cross-sectional view of the right human eye.
  • Fig. 2 is a graph of intraocular pressure response (mm Hg) to 0.1% epinephrine bitartrate, with and without 0.1% dexamethasone.
  • Fig. 3 is a graph of the dose response for concentrations of epinephrine bitartrate from 0.05% to 2% as measured by the difference in mean intraocular pressure (epinephrine minus dexamethasone/epinephrine) at 45 minutes after treatment with epinephrine.
  • Fig. 4 is a graph of the average maximum decrease in ocular pressure from untreated pressure (mm Hg) following application of 0.1% dexamethasone in combination with epinephrine at a concentration between 0.001% and 0.1%.
  • Fig. 5 is a graph of the effect of varying doses of epinephrine and dexamethasone on the average decrease of ocular pressure up to the maximum pressure difference, expressed as the difference between dexamethasone plus epinephrine minus epinephrine alone, compared to the average pressure prior to epinephrine application.
  • Fig. 6 is a graph of the duration of the effect on ocular pressure of treatment with dexamethasone at a concentration between 0.001% and 0.1% combined with epinephrine at a concentration between 0.001% and 0.1% versus epinephrine alone at a concentration between 0.001% and 0.1%.
  • the present invention is the treatment of glaucoma with two drugs: a corticosteroid such as dexamethasone and an adrenergic agent.
  • a number of adrenergic agents are useful in the present invention, including both alpha and beta agonists such as epinephrine, dipivalyl epinephrine and other epinephrine salts, and alpha and beta antagonists such as timolol, butaxolol, levobunolol, and various combinations of these drugs.
  • alpha and beta agonists such as epinephrine, dipivalyl epinephrine and other epinephrine salts
  • alpha and beta antagonists such as timolol, butaxolol, levobunolol, and various combinations of these drugs.
  • Epinephrine bitartrate is a standard drug used in the treatment of glaucoma. Epinephrine reduces the rate of aqueous humor formation and improves the facility of outflow of aqueous humor. This improved facility is not immediate but may be observed after several months of topical epinephrine therapy. Epinephrine and dipivalyl epinephrine are useful in the management of chronic simple (open-angle) glaucoma, either alone or in combination with iotics such as pilocarpine, carbonic anhydrase inhibitors, or beta receptor blockers such as timolol.
  • epinephrine When applied in the absence of corticosteroids, in the conventional manner, epinephrine is topically applied as a sterile aqueous 2% solution on an individual basis, ranging from twice daily to once every two or three days. More frequent instillation than one drop four times daily does not usually elicit any further improvement in therapeutic response.
  • Dipivalyl epinephrine is conventionally applied as a 0.1% solution.
  • Betaxolol and levobunolol are typically applied as a 0.5% solution.
  • Timolol is applied as a 0.25 or 0.5% solution.
  • lower concentrations are used due to the enhancing effect of the corticosteroid. This has the advantage of decreasing the incidence or severity of side effects due to the adrenergic agent.
  • corticosteroids examples include dexamethasone, prednisone, prednisolone, hydrocortisone, cortisone, fludrocortisone, betamethasone, methyl prednisone, triamcinolone, and their derivatives.
  • Dexamethasone sodium phosphate and other corticosteroids are conventionally used for the treatment of steroid-responsive inflammatory conditions such as allergic conjunctivitis, superficial punctate keratitis, herpes zoster keratitis, corneal injury from chemical or thermal burns, and in other situations where an inflammatory response has been incited by mechanical, chemical or immunological agents.
  • steroid-responsive inflammatory conditions such as allergic conjunctivitis, superficial punctate keratitis, herpes zoster keratitis, corneal injury from chemical or thermal burns, and in other situations where an inflammatory response has been incited by mechanical, chemical or immunological agents.
  • one or two drops of a 0.1% dexamethasone phosphate solution are topically applied to the eye between three and four times a day up to once every hour, depending on the treatment required. Prolonged use must be avoided as the dexamethasone causes increased ocular pressure over time. People on systemic corticosteroids frequently also exhibit
  • Medications are routinely applied to the eye by means of a dropper. Variations in the actual amount delivered to the eye will vary somewhat according to the shape and size of the dropper and the skill of the person administering the drops.
  • dexamethasone has been demonstrated to enhance the effectiveness of epinephrine in decreasing intraocular pressure, allowing the use of lower concentrations of epinephrine to achieve the same decrease in pressure. Since the mechanism by which this occurs involves an enhancement in the number, binding affinity, or some other function of the adrenergic receptors by the corticosteroids, other corticosteroids may be used with other adrenergic agents to produce the same result. The advantages are immediately noticeable, most significant being the decrease in both systemic and local side effects due to the adrenergic agent.
  • the preferred treatment of glaucoma is to pretreat the eye with a solution of less than 0.1% dexamethasone followed by topical application of a less than 2% solution of epinephrine or a less than 0.1% solution of dipivalyl epinephrine.
  • the decrease of intraocular pressure is a function of the interaction of the two drugs. They may be applied in combination or in sequence.
  • This invention is further illustrated by the following non-limiting examples.
  • rabbit eyes were treated with a combination of dexamethasone and epinephrine to decrease ocular pressure. Rabbits are the standard model for testing the reaction of human eyes to drugs or other foreign agents.
  • clinical observations were made on patients suffering from elevated ocular pressures.
  • New Zealand white rabbits were used in a study to measure pressure changes as a function of dexamethasone in combination with epinephrine.
  • the rabbits were acclimated to their new surroundings and frequent handling, including the measurement of intraocular pressure, by having serial intraocular pressure measurements taken daily for four to seven days prior to the beginning of the testing. The experiment was begun only when these daily pressure readings were stable.
  • the intraocular pressure was measured with a Digilab (Cambridge, Massachusetts) pneumatonometer after application of 0.05% proparacaine (Alcaine) for corneal anesthesia.
  • Rabbits were randomized into four groupst a first control group receiving saline placebo drops in both eyes; a second epinephrine group treated with placebo followed by epinephrine bitartrate solution; a third dexamethasone/ epinephrine group receiving a pretreatment with dexamethasone phosphate followed by epinephrine; and a fourth group serving as a second control group, receiving only 0.1% dexamethasone in both eyes.
  • the rabbits' eyes were pretreated with five applications of a single drop of placebo saline or dexamethasone, depending on the protocol of the assigned group. The pretreatment was followed by treatment with placebo or epinephrine. Baseline intraocular pressures were measured at 8t00 a.m., 8t30 a.m., and 9:00 a.m. Placebo or dexamethasone phosphate was administered every 15 minutes from 9:15 a.m. to 10tl5 a.m., for a total of five applications. Intraocular pressure was measured again at 10t30 a.m. At 10:45 a.m., the animals were treated with one drop of either placebo or epinephrine bitartrate topically, and intraocular pressure was subsequently measured about every 30 minutes until 3:00 p.m.
  • concentrations of epinephrine bitartrate used were between 0.001% and 2%.
  • Dexamethasone phosphate was used at concentrations between 0.001% and 0.1%. Both the epinephrine and dexamethasone solutions were prepared at the time of each experiment by dissolving the solute in 0.9% saline solution. The placebo drops were 0.9% saline solution.
  • Fig. 3 plots the dose response to epinephrine, showing the difference in mean ocular pressure between treatment with dexamethasone/epinephrine and treatment with epinephrine alone at 45 minutes after topical epinephrine administration.
  • concentration of epinephrine ranged from 0.05 to 2%.
  • Fig. 4 is a graph showing the average maximum decrease in pressure in relation to pre-epinephrine pressures obtained using 0.1% dexamethasone with varying concentrations of epinephrine, ranging from 0.001 to 0.1%. There is an effect at as low of a concentration as 0.001% epinephrine. However, the effect appears to peak at about 0.01% epinephrine.
  • Test results obtained using 0.01% dexamethasone were comparable to those obtained with 0.1% dexamethasone, as shown in Fig. 5 comparing the average decrease in pressure for 0.1% dexamethasone in combination with epinephrine at a concentration ranging from 0.001% up to 0.1% (left) with the average decrease in pressure for 0.01% dexamethasone and 0.01% dexamethasone in combination with 0.01% epinephrine (right).
  • the pressure decrease was measured as follows. Five measurements were taken of the eye pressure. Dexamethasone was then applied to the eye. followed by application of the epinephrine. The pressure was then measured and the average change in pressure between the initial pressure and the maximum decrease in pressure determined. Epinephrine alone was used as the control?.
  • dexamethasone produces a decrease in ocular pressure of 5.5 mm Hg more than epinephrine alone does. With 0.001% dexamethasone, a decrease in pressure of 3.3 mm Hg more than is produced by epinephrine alone was obtained.
  • Fig. 6 where the duration in minutes versus various concentrations of dexamethasone-epinephrine is graphed.
  • 0.1% dexamethasone was used in combination with epinephrine at a concentration between 0.001% and 0.1%.
  • 0.01% epinephrine was used with two different concentrations of dexamethasone, 0.01% and 0.001%.
  • the duration in decrease of ocular pressure is greater for 0.1% dexamethasone in combination with 0.01% epinephrine than 0.01% dexamethasone in combination with 0.01% epinephrine (240 min. vs. 145 min. ) .
  • the duration is slightly less with 0.001% dexamethasone in combination with 0.01% epinephrine than 0.01% dexamethasone in combination with 0.01% epinephrine (137 min. vs. 145 min.).
  • Part of the therapeutic effectiveness of treatment for glaucoma is to have an eyedrop that has a relatively long duration of effect so that the patient does not have to continuously place eyedrops. Duration is therefore an important consideration.
  • Example 2 Enhanced ocular pressure decrease in a patient on a systemic corticosteroid following topical application of epinephrine.
  • the patient showed a dramatic decrease in ocular pressure in response to 2% epinephrine, twice or more as large as would be expected with 2% epinephrine.
  • the enhanced effect presumably was due to the systemic prednisone therapy.
  • Example 3 Enhanced ocular pressure decrease in a patient on a systemic corticosteroid following topical application of epinephrine in combination with timolol.
  • ocular pressures were 59 mm Hg in the right eye and 40 mm Hg in the left eye. He was placed on 0.25% timolol drops, one twice a day in both eyes.

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Abstract

Une méthode pour traiter le glaucome consiste à exposer l'oeil à un corticostéroïde et ensuite à appliquer à l'oeil un agent adrénergique qui agit pour diminuer la pression oculaire. Parmi les agents adrénergiques utiles on trouve des agonistes et antagonistes alpha et béta, y compris par exemple, l'épinéphrine, l'épinéphrine dipivalyl, le bétaxolol, le lévobunolol et le timolol. Parmi les stéroïdes utiles qui sont de préférence appliqués localement, on trouve la déxaméthasone, la prédnisone, la cortisone et la triamcinolone. Dans le mode de réalisation préféré, une solution de moins de 0,1 % de déxaméthasone et une solution de moins de 2 % d'épinéphrine ou de moins de 0,1 % d'épinéphrine dipivalyl sont localement appliquées sur l'oeil.
PCT/US1986/001862 1986-05-23 1986-09-10 Methode de traitement du glaucome WO1987007141A1 (fr)

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US86660586A 1986-05-23 1986-05-23
US866,605 1986-05-23

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992022300A1 (fr) * 1991-06-18 1992-12-23 Laboratoire Theramex S.A. Compositions oculaires contenant des steroïdes et leur utilisation pour le traitement du glaucome
US5502052A (en) * 1988-04-26 1996-03-26 Alcon Laboratories, Inc. Use of a combination of apraclonidine and timolol to control intraocular pressure
EP1341541A1 (fr) * 2000-11-16 2003-09-10 Alcon Manufacturing Ltd. Therapie combinee abaissant et regulant la tension intraoculaire
WO2005099715A3 (fr) * 2004-04-08 2006-08-03 Retmed Pty Ltd Traitement de pathologies ophtalmiques
US8173707B2 (en) 2002-07-30 2012-05-08 Omeros Corporation Ophthalmologic irrigation solutions and method
US8802128B2 (en) * 2006-06-23 2014-08-12 Allergan, Inc. Steroid-containing sustained release intraocular implants and related methods
US9066856B2 (en) 2012-10-24 2015-06-30 Omeros Corporation Stable preservative-free mydriatic and anti-inflammatory solutions for injection
US11234965B2 (en) 2014-12-01 2022-02-01 Omeros Corporation Anti-inflammatory and mydriatic intracameral solutions for inhibition of postoperative ocular inflammatory conditions

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB755156A (en) * 1953-07-22 1956-08-15 Smith Kline & French Internat Adrenocortical steroid medicinal preparation
US2801202A (en) * 1954-12-24 1957-07-30 Smith Kline French Lab Compositions containing cortisone or hydrocortisone with phenylephrine
US3320125A (en) * 1964-04-28 1967-05-16 Merck & Co Inc Inhalation aerosol composition
US4255415A (en) * 1978-11-22 1981-03-10 Schering Corporation Polyvinyl alcohol ophthalmic gel
US4271143A (en) * 1978-01-25 1981-06-02 Alcon Laboratories, Inc. Sustained release ophthalmic drug dosage

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB755156A (en) * 1953-07-22 1956-08-15 Smith Kline & French Internat Adrenocortical steroid medicinal preparation
US2801202A (en) * 1954-12-24 1957-07-30 Smith Kline French Lab Compositions containing cortisone or hydrocortisone with phenylephrine
US3320125A (en) * 1964-04-28 1967-05-16 Merck & Co Inc Inhalation aerosol composition
US4271143A (en) * 1978-01-25 1981-06-02 Alcon Laboratories, Inc. Sustained release ophthalmic drug dosage
US4255415A (en) * 1978-11-22 1981-03-10 Schering Corporation Polyvinyl alcohol ophthalmic gel

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
Invest. Ophthalmol. Vis. Sci., Volume 24, (suppl.), Number 5, published 1983, (HARRIS), "Dexamethasone-induced Stimulation of Beta-adrenergic Sensitive Adenylate Cyclase in Ciliary Process Epithelium", see entire Abstract. *
Invest. Ophthalmol. Vis. Sci., Volume 26, No. 3 (suppl.), published March 1985, (UNGRICHT), "Enhanced Ocular Hypotensive Response to Epinephrine with prior Dexamethasone Treatment", see entire Abstract. *
Martindale- The Extra Pharmacopoeia, edition 28, published 1982, (London, England), The Pharmaceutical Press, see page 447, Column 2. *
Ocular Pharmacology, edition No. 5, published 1983, (St. Louis, Missouri, USA), (HAVENER), see pages 275-290. *
The Merck Manual of Diagnosis and Therapy, edition No. 14, published 1982, (Rahway, New Jersey, USA), ROBERT BERKOW, "Airways Obstruction", see pages 615-616 and 625-627. *

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5502052A (en) * 1988-04-26 1996-03-26 Alcon Laboratories, Inc. Use of a combination of apraclonidine and timolol to control intraocular pressure
WO1992022300A1 (fr) * 1991-06-18 1992-12-23 Laboratoire Theramex S.A. Compositions oculaires contenant des steroïdes et leur utilisation pour le traitement du glaucome
EP1341541A1 (fr) * 2000-11-16 2003-09-10 Alcon Manufacturing Ltd. Therapie combinee abaissant et regulant la tension intraoculaire
EP1341541A4 (fr) * 2000-11-16 2004-11-17 Alcon Mfg Ltd Therapie combinee abaissant et regulant la tension intraoculaire
US9399040B2 (en) 2002-07-30 2016-07-26 Omeros Corporation Ophthalmologic irrigation solutions and method
US8173707B2 (en) 2002-07-30 2012-05-08 Omeros Corporation Ophthalmologic irrigation solutions and method
US8586633B2 (en) 2002-07-30 2013-11-19 Omeros Corporation Ophthalmologic irrigation solutions and method
US9585895B2 (en) 2002-07-30 2017-03-07 Omeros Corporation Ophthalmologic irrigation solutions and method
US9278101B2 (en) 2002-07-30 2016-03-08 Omeros Corporation Ophthalmologic irrigation solutions and method
WO2005099715A3 (fr) * 2004-04-08 2006-08-03 Retmed Pty Ltd Traitement de pathologies ophtalmiques
JP2008500282A (ja) * 2004-04-08 2008-01-10 レットメッド ピーティーワイ リミテッド 眼症状の治療
US8802128B2 (en) * 2006-06-23 2014-08-12 Allergan, Inc. Steroid-containing sustained release intraocular implants and related methods
US9486406B2 (en) 2012-10-24 2016-11-08 Omeros Corporation Stable preservative-free mydriatic and anti-inflammatory solutions for injection
US9066856B2 (en) 2012-10-24 2015-06-30 Omeros Corporation Stable preservative-free mydriatic and anti-inflammatory solutions for injection
US9855246B2 (en) 2012-10-24 2018-01-02 Omeros Corporation Stable preservative-free mydriatic and anti-inflammatory solutions for injection
US11234965B2 (en) 2014-12-01 2022-02-01 Omeros Corporation Anti-inflammatory and mydriatic intracameral solutions for inhibition of postoperative ocular inflammatory conditions

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