WO2005082374A1

WO2005082374A1 - Predictors for patients at risk for glaucoma from steroid therapy

Info

Publication number: WO2005082374A1
Application number: PCT/AU2005/000263
Authority: WO
Inventors: Gholam A Peyman
Original assignee: Advanced Ocular Systems Limited
Priority date: 2004-02-26
Filing date: 2005-02-25
Publication date: 2005-09-09

Abstract

The present invention provides a method to evaluate a patient's risk for increased intraocular pressure after receiving intraocular steroid therapy comprising the steps of: (a) administering to an eye a steroid at a challenge dose ranging from about 50 µg to about 800 µg; and (b) determining the intraocular pressure changes thereafter.

Description

"Predictors for Patients at Risk for Glaucoma From Steroid Therapy"

Incorporation by Reference

This application claims benefit of United States Patent Application No. 10/787,580 filed 26 February 2004, and Australian Provisional Patent Application No. 2004906931 filed 3 December 2004.

The foregoing applications, and all documents cited therein, together with any manufacturer's instructions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by reference herein, are hereby incorporated herein by reference, and may be employed in the practice of the invention.

Field of the Invention

This invention is directed to a predictive identification of patients at risk for ophthalmic administration of steroids. More specifically, the invention relates to low-dose ophthalmic administration of triamcinolone acetonide.

Background Art

Patients undergoing treatment for intraocular pathologies are frequently treated with corticosteroids. For example, the steroid triamcinolone is administered to patients undergoing photodynamic therapy for diseases such as macular edema, uveitis, and age related macular degeneration. It is also administered for treatment of proliferative diabetic retinopathy, idiopathic juxtafoveal telangiectasias, macular edema secondary to diabetes mellitus, central retinal vein occlusion, pseudophakia, uveitis, and pseudophakic CME. Intraoperatively, it is used for visualization of the posterior hyaloid. These patients may receive doses of triamcinolone ranging from about 1 mg up to about 8 mg.

Increased intraocular pressure, termed glaucoma or ocular hypertension, is an undesirable and serious side effect of ocular steroid therapy. In addition, neovascular glaucoma results from increased growth and/or proliferation of blood vessels within the eye (intraocular neovascularization). This leads to hemorrhage and fibrosis, and results in structural damage to the eye with subsequent decreased visual acuity. The higher the dose of triamcinolone administered, the higher the risk for glaucoma. In about 10% of patients, glaucoma develops to a degree where surgical intervention is required to reduce the intraocular pressure to within normal levels.

Increased intraocular pressure after intravitreal TA injection has been well documented. Jonas et al. [Jonas JB, Kreissig I, Degenring R. Intraocular pressure after intravitreal triamcinolone injection. Br J Ophthalmol. 2003; 87: 24- 27] showed that an IOP elevation occurred 1 to 2 months post 25 mg intravitreal TA injection in 50% of eyes. Bakri et al. [Bakri SJ, Beer PM. The effect of intravitreal triamcinolone acetonide on intraocular pressure. Ophthalmic Surgery, Lasers, and Imaging. 2003; 34:386-390.] found that a single 4mg intravitreal TA resulted in an increase in intraocular pressure of 5 mmHg or greater in 48.8% of eyes after initial injection, with pressures > 10 mm Hg developing in 27.9% of eyes.

Triamcinolone therapy has also been reported to cause adverse events. One multicenter study reported a 0.87% incidence of endophthalmitis, proven by positive cultures, with 922 consecutive intravitreal triamcinolone injections. Another study reported an increase in intraocular pressure in 30%-4O% of patients treated with 1 mg, 2 mg, or 4 mg triamcinolone. Another study reported increased intraocular pressure in 50% of eyes one to two months after intravitreal injections of 25 mg triamcinolone acetonide. Another study reported that a single 4 mg intravitreal injection of triamcinolone acetonide resulted in a transient rise in intraocular pressure in 48.8% of patients, with high intraocular pressure developing in 27.9% of these patients

For any patient, but particularly for patients with a pre-existing ocular disease, the risk of proceeding with triamcinolone therapy, versus an alternative therapy that may be less efficacious, must be carefully considered and the resulting risks and benefits must be understood and evaluated. In patients already suffering from glaucoma or at risk for developing glaucoma, the risk of further exacerbation is unacceptable and should be prevented. Given the potential damaging consequences of even some short-term elevations in intraocular pressure, the ability to identify patients at risk of developing ocular hypertension or glaucoma after intravitreal TA injection could be a useful tool in clinical practice before a particular therapeutic regimen is initiated. Identifying patients at risk would allow an alternative therapy to be considered. It would also provide assurance to physicians, as well as patients undergoing intraocular steroid therapy, of a decreased likelihood for developing glaucoma as a result of treatment.

Summary of the Invention

The present invention provides a method to evaluate a patient's risk for the increased intraocular pressure that is known to occur in some patients receiving intraocular steroid therapy. In particular, the invention provides a method to evaluate a patient's risk for increased intraocular pressure after receiving intraocular steroid therapy comprising the steps of: (a) administering to an eye a steroid at a challenge dose ranging from about 50 μg to about 800 μg; and (b) determining what the intraocular pressure is in the eye after delivery of the challenge dose.

According to the method a steroid such as triamcinolone is administered at a challenge dose ranging from about 50 μg to about 800 μg, and the intraocular pressure is thereafter determined. In one embodiment, about 400 μg triamcinolone is administered. An intraocular pressure of at least 5 mm Hg higher after the challenge dose than an intraocular pressure before the challenge dose indicates that the patient would likely have increased intraocular pressure if a therapeutic dose of a steroid, such as about 4 mg to about 8 mg triamcinolone, were administered. The physician will then be better able to evaluate the benefits and risks of this therapy versus alternate therapy. The challenge dose may be injected into the vitreous of the eye, or it may be injected into another area or site in the eye, or it may be implanted in the eye, etc.

In an alternate embodiment, a patient to be treated with a steroid for macular degeneration, macular edema, diabetic retinopathy, or another ocular disease, receives an intraocular challenge with triamcinolone. The patient's intraocular pressure before and at an interval after the challenge dose is compared. A patient is considered at risk, and thus alternative therapy may be considered, if the intraocular pressure after the challenge is 5 mm Hg or more than the patient's intraocular pressure before the challenge.

In an alternate embodiment, a patient's risk of increased intraocular pressure with intraocular steroid therapy is assessed by comparing the patient's intraocular pressure before and from one day to three months after an intravitreal injection of a challenge triamcinolone dose. An increased intraocular pressure of at least 5 mm Hg after the challenge dose indicates a risk for increased intraocular pressure after a higher therapeutic steroid dose.

In any embodiment, non-toxic amounts of anti-angiogenic agents, such as low molecular weight heparin and/or doxycycline, may also be administered to provide other beneficial effects to the patient.

Other objects, features, and advantages of the instant invention, in its details as seen from the above, and from the following description when considered in light of the appended claims.

Disclosure of the Invention

General

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. The invention includes all such variation and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in the specification, individually or collectively and any and all combinations or any two or more of the steps or features.

Each document, reference, patent application or patent cited in this text is expressly incorporated herein in their entirety by reference, which means that it should be read and considered by the reader as part of this text. That the document, reference, patent application or patent cited in this text is not repeated in this text is merely for reasons of conciseness. The present invention is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only. Functionally equivalent products, compositions and methods are clearly within the scope of the invention as described herein.

The invention described herein may include one or more range of values (eg size, concentration etc). A range of values will be understood to include all values within the range, including the values defining the range, and values adjacent to the range which lead to the same or substantially the same outcome as the values immediately adjacent to that value which defines the boundary to the range.

Throughout this specification, unless the context requires otherwise, the word "comprise" or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. It is also noted that in this disclosure and particularly in the claims and/or paragraphs, terms such as "comprises", "comprised", "comprising" and the like can have the meaning attributed to it in U.S. Patent law; e.g., they can mean "includes", "included", "including", and the like; and that terms such as "consisting essentially of" and "consists essentially of" have the meaning ascribed to them in U.S. Patent law, e.g., they allow for elements not explicitly recited, but exclude elements that are found in the prior art or that affect a basic or novel characteristic of the invention.

Other definitions for selected terms used herein may be found within the description of the invention and apply throughout. Unless otherwise defined, all other scientific and technical terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the invention belongs.

Detailed Disclosure of the invention

Patients who are candidates for steroid therapy to treat an ocular disease, or patients already being treated with steroids for an ocular disease, are evaluated for their risk of developing increased intraocular pressure, which is a known side effect of steroid therapy. Triamcinolone acetonide (Kenacort®, Kenalog® (Bristol-M yers Squibb, Princeton NJ)) administered intravitreally in a challenge dose ranging from about 50 μg to about 800 μg may determine patients at risk for developing a steroid- induced increase in intraocular pressure when these patients are administered a therapeutic dose of triamcinolone by intravitreal injection. For example the challenge dose may be 50 μg, 100 μg, 150 μg, 200 μg, 250 μg, 300 μg, 350 μg, 400 μg, 450 μg, 500 μg, 550 μg, 600 μg, 650 μg, 700 μg, 750 μg, or 800 μg, or any amount within these illustrated doses

A patient who tolerates a challenge dose without a significant increase in intraocular pressure is less likely to have a pressure elevation with a therapeutic dose, for example, 4 mg or 8 mg triamcinolone. Properties of intraocular pressure (e.g., rate of pressure increase, extent of pressure increase, etc.) are assessed as predictors of the extent and severity of increased intraocular pressure if higher therapeutic doses were administered. The physician may evaluate these risks and benefits and make a better-informed decision.

One risk factor for development of glaucoma after intravitreal injections of triamcinolone or another steroid is a patient's preexisting history of primary open-angle glaucoma. However, patients who are candidates for steroid therapy for other diseases, or who receive steroid therapy for other indications, may be at risk, but may not be aware of their risk. The invention permits an evaluation and determination of which patients are at risk and in whom the desirability of steroid therapy must be further evaluated from a risk/benefit perspective. Once identified, these patients may then be prescribed other therapies so that their risk for developing increased intraocular pressure is reduced or eliminated.

Triamcinolone is frequently administered to treat ocular pathologies such as macular edema, uveitis, age related macular degeneration, diabetic retinopathy, idiopathic juxtafoveal telangiectasias, macular edema secondary to diabetes mellitus, central retinal vein occlusion, and pseudophakia or for other indications such as intraoperative visualization of the posterior hyaloid. For example, triamcinolone at a dose in the range of about 4 mg to about 8 mg may be injected into the vitreous of the eye (intravitreous administration). These doses result in increased intraocular pressure in about 10% of the treated patients. ln one embodiment, a test dose of triamcinolone acetonide (9α-fluoro-11 β, 16α, 17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone (C₂ H₃ιF0₆)) is intraocularly administered to a patient, and the intraocular pressure is determined. Triamcinolone is a glucocorticoid with a molecular weight of 434.51. The test dose of triamcinolone that is administered is in the range of about 50 ug to about 800 ug. The test dose may be administered in any formulation, such as a slow release formulation, a carrier formulation such as microspheres, microcapsules, liposomes, etc., an intravenous solution, topical administration or suspension, or an intraocular injection, as known to one skilled in the art.

A time-release drug delivery system may be administered intraocularly to result in sustained release of the agent over a period of time. The formulation may be in the form of a vehicle, such as a micro- or rnacro-capsule or matrix of biocompatible polymers such as polycaprolactone, polyglycolic acid, polylactic acid, polyan hydrides, polylactide-co-glycolides, polyamino acids, polyethylene oxide, acrylic terminated polyethylene oxide, polyamides, polyethylenes, polyacrylonitriles, polyphosphazenes, po!y(ortho esters>, sucrose acetate isobutyrate (SAIB), and other polymers such as those disclosed in U.S. Patent Nos. 6,667,371 ; 6,613,355; 6,596,296; 6,413,536; 5,968,543; 4,079₃038; 4,093,709; 4,131,648; 4,138,344; 4,180,646; 4,304,767; 4,946,931, each of which is expressly incorporated by reference herein in its entirety, or lipids that may be formulated as microspheres or liposomes. A microscopic or macroscopic formulation may be administered through a needle, or may be implanted by suturing within the eye, for example, within the lens capsule. Delayed or extended release properties may be provided through various formulations of the vehicle (coated or uncoated micnosphere, coated or uncoated capsule, lipid or polymer components, unilamellar or multilamellar structure, and combinations of the above, etc.). The formulation and loading of microspheres, microcapsules, liposomes, etc. and their ocular implantation are standard techniques known by one skilled in the art, for example, the use a ganciclovir sustained-release implant to treat cytomegalovirus retinitis, disclosed in Vitreoretinal Surgical Techniques, Peyman et al., Eds. (Martin Dunitz, London 2001, chapter 45); Handbook of Pharmaceutical Controlled Release Technology, Wise, Ed. (Marcel Dekker, New York 2000), the relevant sections of which are incorporated by reference herein in their entirety. For example, a sustained release intraocular implant may be inserted through the pars plana for implantation in the vitreous cavity. An intraocular injection may be into the vitreous (intravitreal), or under the conjunctiva (subconjunctival), or behind the eye (retrobulbar), or under the Capsule of Tenon (sub-Tenon), and may be in a depot form. Other intraocular routes of administration and injection sites and forms are also contemplated and are within the scope of the invention.

The extent of risk for a patient with a pre-existing history of primary open angle glaucoma after intravitreal triamcinolone acetonide injection may be difficult to predict. Nonetheless, intravitreal steroid therapy for patients with glaucoma presents a risk that must be considered in determining whether to treat with triamcinolone or other steroids.

In another embodiment of the invention, a challenge dose of a steroid is intraocularly administered with one or more inhibitors of angiogenesis. One inhibitor of angiogenesis is low molecular weight heparin. Another inhibitor of angiogenesis is the antibiotic doxycycline.

The effect of a particular steroid, hydrocortisone 21 -phosphate, with low molecular weight heparin in inhibiting neovascularization in the cornea has been reported (Lepri et al., J. Ocular Pharmacol. 10, 273, 1994, which is expressly incorporated by reference herein it its entirety). There was about a 60% reduction in the amount and length of blood vessels when hydrocortisone and low molecular weight heparin were administered to rats at a dose of two drops per eye, four times daily, for six days. However, this evaluation was in vitro (reduction in vascular area was evaluated in enucleated rat corneas), and thus did not address the issues of toxicity or the effect on visual acuity in a living human patient. It also did not address the effect of intraocular pressure. Further, it did not evaluate triamcinolone, which is a frequently prescribed steroid for ocular pathologies in human patients.

Low molecular weight heparin refers to heparin with a molecular weight of around 1000 Daltons. Low molecular weight heparin may be heparin sulfate, a lower- sulfated, higher-acetylated form of heparin. All of these are commercially available (e.g., Sigma Aldrich, St. Louis MO). ln one embodiment, a challenge dose of steroids such as betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, and/or triamcinolone, and low molecular weight heparin may be administered. The route and form of administration may be any method known to one skilled in the art, and as previously described.

In one embodiment, the steroid(s) and anti-angiogenic agent(s) are intraocularly injected, for example, into the vitreous. The steroid(s) and anti-angiogenic agent(s) may be administered as a mixture, an admixture, in the same formulation, in separate formulations, etc. The dose of steroid administered is in the range of about 50 μg to about 800 μg. In one embodiment, the dose of steroid is about 400 μg-

The anti-angiogenic agent is administered with the steroid in an amount that does not result in intraocular toxicity. For example, low molecular weight heparin may be administered in a concentration ranging from about 0.5 mg/ml to about 20 mg/ml (for example, administration of 0.1 ml of a 100 mg/ml formulation of low molecular weight heparin). In various embodiments, the concentration may be about 0.5 mg/ml to about 2.5 mg/ml, about 1 mg/ml to about 5 mg/ml, or about 5 mg/ml to about 10 mg/ml. Any concentration within these ranges may be used. Doxycycline may range from about 0.05 mg to about 1 mg. These doses are substantially non- toxic to the patient. Besides its anti-angiogenic effect, doxycycline in a steroid challenge administration could reduce the incidence of endophthalmitis, which occurs in about 0.5% of eyes in which a steroid is administered.

In addition to assessing a patient's risk for increased intraocular pressure, this embodiment also reduces or eliminates the risk of ocular neovascularization. The growth or proliferation of new blood vessels (neovascularization) in the eye may occur in patients with diabetes, uveitis, and age related macular degeneration. This is undesirable, for example, because new vessels may occlude the cornea or other structures, leading to reduced vision. A possible mechanism for the beneficial effect of low molecular weight heparin in reducing vessel growth and proliferation is its polyanionic structure, which readily binds to polycationic angiogenic factors. Angiogenic factors with heparin bound to them have reduced biological activity, and therefore do not promote new vessel growth. A possible mechanism for the beneficial effects of doxycycline is its inhibition of metalloproteinases, which promote neovascularization.

Other variations or embodiments of the invention will also be apparent to one of ordinary skill in the art from the above descriptions. Thus, the forgoing embodiments are not to be construed as limiting the scope of this invention.

Examples

Further features of the present invention are more fully described in the following non-limiting Examples. It is to be understood, however, that this detailed description is included solely for the purposes of exemplifying the present invention. It should not be understood in any way as a restriction on the broad description of the invention as set out above.

Example 1

Method

Twenty-seven patients received a challenge intravitreal injection of 400 μg triamcinolone acetonide. Visual acuity and intraocular pressure (IOP) were documented prior to the challenge injection; this intraocular pressure served as the control pressure.

Eight patients had macular edema that was clinically significant, six patients had cystoid macular edema, and thirteen patients had age-related macular degeneration. Fourteen patients were pseudophakic, and thirteen patients were phakic.

Of the twenty-seven patients evaluated, three patients had diagnosed primary open angle glaucoma. These patients were medically treated with Alphagan and Xalatan, Timolol, and Xalatan, respectively. None of these three patients had a prior history of filtering surgery for removal of the aqueous to reduce intraocular pressure. Topical alcaine was applied to the ocular surface, followed by 5% povidone iodine. A cotton-tipped applicator soaked in 4% lidocaine was then applied to the injection site, which was 4.0 mm posterior to the limbus in phakic eyes and 3.5 mm posterior to the limbus in pseudophakic eyes. A 27-gauge needle was used for injection at the superior pars plana. Indirect ophthalmoscopy confirmed proper intravitreal placement of the suspension.

The challenge dose was prepared in a pharmaceutically acceptable formulation by diluting triamcinolone acetonide in a sterile balanced salt solution. For example, a 400 μg challenge dose was prepared by diluting 0.1 ml triamcinolone acetonide in 0.9 ml of sterile balanced salt solution, with an injection volume of 0.1 ml.

All patients had an anterior chamber tap performed with a 30 gauge needle after the challenge injection. This served to lower and normalize the intraocular pressure so that subsequent increases in intraocular pressure could be attributed to the challenge dose alone. Intraocular pressure was measured using Goldmann applanation at the following times post-challenge injection: 1 or 2 days, 1 week, and 1 to 3 months.

Patients in which the intraocular pressure did not increase by at least 5 mm Hg by days 1 or 2 were given a second intravitreal injection of either 4 mg or 8 mg triamcinolone acetonide at varying time periods. Patients in which the intraocular pressure did increase by at least 5 mm Hg were not given a second injection of triamcinolone acetonide.

Results

Three of the twenty-seven patients had preexisting glaucoma. Of these three, only one (33%) showed an increase in intraocular pressure. This patient had the greatest increase in intraocular pressure (an increase of 25 mm Hg).

Of the twenty-seven patients receiving the triamcinolone acetonide challenge, four (15%) showed an increase in intraocular pressure greater than 5 mm Hg by day 1 post- challenge injection. Of these four patients, one was the patient previously described with a history of primary open-angle glaucoma and an increase in intraocular pressure of 25 mm Hg. A second patient, who was a diabetic with clinically significant macular edema, had an increase in intraocular pressure of 8 mm Hg by day 1. A third patient, with wet age-related macular degeneration , had an increase in intraocular pressure of 7 mm Hg by day 1. A fourth patient, with wet age related macular degeneration, had an increase in intraocular pressure of 5 mm Hg by day 1. All four eyes returned to pre-injection intraocular pressures with topical anti- glaucoma therapy.

The remaining twenty-three patients received a second injection of high dose triamcinolone acetonide. Only two patients (8.7%) had an increase in intraocular pressure greater than 5 mm Hg within three months of the post-challenge injection. One of these patients, who had wet age-related macular degeneration, received a dose of 4 mg triamcinolone and had an increase in intraocular pressure of 6 mm Hg on post-challenge injection day 24. The other patient, who had cystoid macular edema, received a dose of 8 mg triamcinolone and had an increase in intraocular pressure of 5 mm Hg on post-challenge injection day 1. These two patients had intraocular pressures that returned to their pre-injection pressures with topical anti- glaucoma agents. Neither patient had a history of primary open angle glaucoma.

The six patients under evaluation who were treated with topical anti-glaucoma medications had normal intraocular pressure within one to two months. The anti- glaucoma medication was discontinued except for the patient with a pre-existing history of primary open angle glaucoma. This patient was maintained on Cosopt, Alphagan, and Xalatan, and the patient's intraocular pressure was 12 mm Hg at eight weeks post-injection challenge with 400 μg triamcinolone acetonide. As previously stated, the 25 mm Hg increase in intraocular pressure was ihe most significant increase and was seen as early as one day after a single chal lenge injection (400 μg). Had this patient received a therapeutic dose of triamcinolone acetonide (for example, 4 mg or 8 mg), the intraocular pressure would likely be greater and last longer. This response indicates a propensity for patients with a history of glaucoma to respond to intravitreal steroids. The other two glaucoma patients, however, showed no increase in intraocular pressure after the challenge dose. These patients were administered subsequent doses of 4 mg and 8 mg triamcinolone acetonide, respectively, and did not develop increased intraocular pressure up to twelve weeks post-challenge.

Of the twenty-seven patients receiving a second injection with a therapeutic dose of 4 mg or 8 mg, only two (8.7%) had an increase in intraocular pressure of at least 5 mm Hg within thirty days. These patients were successfully treated with topical medication, which was discontinued by the end of the study. Had these patients not been identified as requiring treatment, however, the outcome may have been more severe.

Example 2

Method

All 83 eyes in this study were treated with 400ug of intravitreal TA at enrolment. Indications for injection included 26 eyes with diabetic macular edema, 15 with pseudophakic CME, 38 with neovascular AMD, 1 with macular edema associated with branch retinal vein occlusion, 1 macular edema associated with central retinal vein occlusion, 1 with retinal angiomatous proliferation (RAP), and 1 with uveitis.

An IRB approved informed consent was obtained for each patient. Snellen visual acuity and Goldmann applanation intra ocular pressure (IOP) in both eyes were documented for each patient prior to injection. The pre-injection IOP of each eye served as the control pressure.

Three of the patients enrolled had a pre-existing diagnosis of primary open angle glaucoma (POAG) with medically controlled IOP. The three involved eyes of these patients were being treated with Alphagan and Xalatan, Timolol, and Xalatan, respectively. None of these three eyes had prior history of surgery or laser for glaucoma. The injection technique was as follows:

Topical proparacaine was applied to the ocular surface followed by a preparation of 5% povidone iodine. A cotton-tipped applicator soaked in 4% lidocaine was then applied to the injection site. An injection site was chosen 4.0mm posterior to the limbus in phakic eyes and 3.5mm posterior to the limbus in pseudophakic eyes. A 27 gauge needle was used for injection at the superior pars plana. A 400ug dose of TA was prepared by diluting 0.1 ml of a solution of 40 mg/ml of TA in 0.9 ml of sterile balanced salt solution. A 0.1 ml volume of this preparation was then injected. Indirect ophthalmoscopy was used to confirm proper intravitreal placement of the suspension and the absence of posterior segment complications. Topical antibiotics were prescribed for each eye.

The IOP was measured at 1 or 2 days, 1 week, 1 month, and at varying intervals from 2 to 7 months post-injection by Goldmann applanation. An early rise was defined as an increase of at least 5 mm Hg in IOP within the first week after 400 ug intravitreal TA injection. A late rise was defined as an increase of at least 5 mm Hg anytime after the high dose 4 or 8 mg injection. Eyes without an early rise in IOP were given a second intravitreal injection of either -4 or 8 mg of TA. Eyes with an early rise in IOP were not given a subsequent higher dose of TA.

Nineteen of these 83 eyes have been followed greater than 6 months to date; 30 eyes for 3 to 6 months; 11 eyes for 2 months; 14 eyes for "1 month; and 9 eyes for less than 1 month.

Results:

Seven of the 83 eyes in the study (8.5%) had an early rise in IOP. Of the three study eyes known to be glaucomatous, only one eye demonstrated an early rise. The elevation in IOP in this eye was 25 mm Hg, however tine range of elevation in IOP in the non-glaucomatous early rise eyes was from 5 to 13 mm Hg; the average early rise in IOP was 10.0 mm Hg in the 7 early rise eyes. These early rises were noted as early as day one post injection. Based on this early rise, these eyes did not receive the full dose of intravitreal TA injection. IOP in all early rise eyes returned to pre-injection intraocular pressure with only topical glaucoma agents by 2 months.

Of the 76 eyes that qualified for a second, full dose, injection of TA, 12 eyes had a late rise in IOP (16%). Of these 12 eyes, 8 eyes had received a dose of 4 mg TA, while 4 eyes had received 8 mg TA. Initial late rise responses were noted from 2 days to 7 months post-injection. In all eyes, IOP returned to pre-injection level with only topical glaucoma agents by 2 months. Two of these 11 eyes had a history of primary open angle glaucoma. The average IOP elevation was 9.8 mm Hg, ranging from 6 to 20 mm Hg.

Of the 68 eyes receiving the 4 mg full dose of TA, 8 eyes (12%) were in the late rise group. Of the 8 eyes receiving the 8 mg full dose of TA, 4 eyes (50%) were in the late rise group. The difference in late IOP response between the 4 mg and 8 mg TA dosages was statistically significant (p, 0.02 with Fisher's exact test)

Forty nine eyes were followed for at least 3 months after full dose injection of TA. Follow up in this group ranged from 3 to 11 months. Of these 49 eyes, 12 eyes (24%) had a late rise. The average maximum IOP elevation in this late rise group was 9.8 mm Hg (range 6 to 20 mm Hg) and occurred from 3 weeks to 6 months post full dose injection. The eye achieving a 20 mm Hg elevation in IOP was non glaucomatous, and reached its maximum rise 4 weeks after full dose injection. The two glaucomatous eyes in this group demonstrated an average IOP elevation of 10.5 mm Hg. As stated previously, all IOP elevations were successfully treated with topical agents alone.

A subset of 21 eyes received more than one full dose injection. Eighteen eyes received 2 injections of 4mg each; 2 eyes received 3 injections of 4 mg each; 1 eye received 4 injections, comprised of one 8mg injection and three 4mg injections. None of the eyes receiving multiple full dose injections demonstrated a significant rise in IOP.

The average baseline IOP of the 7 early rise eyes was 16.6 mm Hg. The average baseline IOP of the 49 eyes receiving the full dose injections and followed for at least 3 months postoperatively was 14.5 mm Hg. The average baseline IOP of the 12 late rise eyes was 14.6 mm Hg. The average maximum IOP elevation of the nonresponders in the study was < 1 mm Hg, whereas average maximum IOP elevation in the early rise group was 10.0 mm Hg, and of the late rise group was 9.8 mm Hg.

After 173 intravitreal injections, one eye had a sterile endophthalmitis (0.6%) and none had infectious endophthalmitis.

Claims

The Claims Defining the Invention are as Follows

1. A method to evaluate a patient's risk for increased intraocular pressure after receiving intraocular steroid therapy comprising the steps of: (a) administering to an eye a steroid at a challenge dose ranging from about 50 μg to about 800 μg; and (b) determining what the intraocular pressure is in the eye after delivery of the challenge dose.

2. A method according to claim 1 wherein the steroid is selected from the group consisting of betamethasone, budesonide, cortisone, dexamethason e, hydrocortisone, methylprednisolone, prednisolone, prednisone, and/or triamcinolone.

3. A method according to claim 1 wherein the steroid is triamcinolone or a derivative thereof.

4. A method according to claim 3 wherein the triamcinolone is triamcinolone acetonide.

5. A method according to claim 3 wherein the dose of triamcinolone is selected from the following list of doses: 50μg, 100μg, 150μg, 200μg, 250μg, 300μ g, 350μg, 400μg, 450μg, 500μg, 550μg, 600μg, 650μg, 700μg, 750μg, or 800μg.

6. A method according to claim 1 , wherein the challenge dose is intraocularly delivered.

7. A method according to claim 1 , wherein the challenge dose is injected into the vitreous of the eye.

8. A method according to claim 1 , wherein the challenge dose is injected into a region of the eye which leads to passage of the dose into the vitreous

9. A method according to claim 1 , wherein the challenge dose is implanted in the eye.

10. A method according to claim 1 , wherein determination of the intraocular pressure is established by measuring the patient's intraocular pressure before and at an interval after delivery of the challenge dose.

11. A method according to claim 10, wherein the patient's intraocular pressure is determined from one day to three months after an intravitreal injection of a challenge dose.

12. A method according to claim 1 , wherein an intraocular pressure of at least 5 mm Hg higher after the challenge dose than an intraocular pressure before the challenge dose indicates that the patient would likely have increased intraocular pressure if a therapeutic dose of a steroid, such as about 4 mg to about 8 mg triamcinolone, were administered.

13. A method according to anyone of claims 1 to 12 wherein the challenge dose includes, non-toxic amounts of at least an anti-angiogenic agent at doses that are therapeutically effective to treat an ocular ailment.

14. A method according to claim 13, wherein the anti-angiogenic agent is low molecular weight heparin at doses that are therapeutically effective to treat an ocular ailment.

15. A method according to claim 14, wherein the low molecular weight heparin is administered in a concentration ranging from about 0.1 mg/ml to about 100 mg/ml.

16. A method according to claim 14, wherein the low molecular weight heparin is administered in a concentration ranging from about 0.5 mg/ml to about 20 mg/ml.

17. A method according to claim 14, wherein the low molecular weight heparin is administered in a concentration ranging from about 0.5 mg/ml to about 2.5 mg/ml.

18. A method according to claim 14, wherein the low molecular weight heparin is administered in a concentration ranging from about 1 mg/ml to about 5 mg/ml.

19. A method according to claim 14, wherein the low molecular weight heparin is administered in a concentration ranging from about or about 5 mg/ml to about 10 mg/ml.

20. A method according to claim 13, wherein the anti-angiogenic agent is doxycycline at doses that are therapeutically effective to treat an ocular ailment.

21. A method according to claim 20, wherein the doxycycline is administered in a concentration ranging from about 0.05 mg to about 1 mg.

22. A method according to claims 13, wherein the anti-angiogenic agent includes low molecular weight heparin and doxycycline at doses that are therapeutically effective to treat an ocular ailment.

23. A method according to anyone of claims 1 to 22, wherein the challenge dose is administered as a slow release formulation

24. A method according to anyone of claims 1 to 22, wherein the challenge dose is administered in a carrier formulation such as microspheres, microcapsules, liposomes.