Volume 4, Number 7
July 2008



Contents:
WELCOME
THE LATEST PUBLISHED RESEARCH
NOTEWORTHY: FDA APPROVES TRIAMCINOLONE FORMULATION FOR INTRAVITREAL INJECTION; FDA APPROVES TOPICAL STEROID FOR POSTOP INFLAMMATION AND PAIN; AND OTHER ITEMS OF INTEREST






WELCOME

Welcome to Review of Ophthalmology’s Retina Online newsletter. Each month, Medical Editor Philip Rosenfeld, MD, PhD, and our editors provide you with this timely and easily accessible report to keep you up to date on important information affecting the care of patients with vitreoretinal disease.

In this edition:
The latest published research
Noteworthy, items of interest

Table of Contents





THE LATEST PUBLISHED RESEARCH

Different Doses of Intravitreal Triamcinolone for Refractory Diffuse DME
In a recent study, a 4-mg dose of intravitreal triamcinolone was not more effective than a 1-mg or 2-mg dose for the treatment of eyes with refractory diffuse diabetic macular edema (DME) and cystic changes. In the study, 45 eyes of 45 patients with diffuse DME were randomized to receive 1, 2 or 4 mg of triamcinolone and followed for six months. Forty-two patients completed the six months of follow-up and were included in the analysis.

At four weeks after injection, central macular thickness improved and Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity improved by eight to nine letters in all three groups. The improvements were maintained through 12 and 24 weeks in the 1- and 2-mg groups, but not in the 4-mg group, where results were significantly worse (p=0.01, 0.03, 0.01 and 0.05).

Source: Hauser D, Bukelman A, Pokroy R, et al. Intravitreal triamcinolone for diabetic macular edema: comparison of 1, 2, and 4 mg. Retina 2008;28(6):825-830.


Rosiglitazone Appears to Delay Onset of Proliferative Diabetic Retinopathy
Based on the results of their study, researchers at Harvard Medical School concluded that rosiglitazone maleate (Avandia, GlaxoSmithKline), a drug used in the treatment of diabetes, may delay the onset of proliferative diabetic retinopathy (DR), possibly because of its antiangiogenic activity. The study was a longitudinal medical record review of all patients treated with rosiglitazone receiving medical and ophthalmic care at the Joslin Diabetes Center from May 1, 2002 to May 31, 2003 (124 patients) and matched control patients not taking a glitazone drug (158 patients). Mean follow-up time was 2.8 years. Baseline characteristics and final hemoglobin A1c values were similar in the rosiglitazone and control groups.

In eyes with severe nonproliferative DR at baseline (rosiglitazone group, 14 eyes; control group, 24 eyes), progression to proliferative DR over three years occurred in 19.2 percent of the rosiglitazone group and 47.4 percent of the control group, representing a 59 percent relative risk reduction. Fewer eyes in the rosiglitazone group experienced three or more lines of visual acuity loss. The incidence of DME was similar in both groups.

The authors of the study paper suggested that future clinical investigations consider analysis of this potential benefit as well as the potential cardiac risks associated with rosiglitazone.

Source: Shen LQ, Child A, Weber GM, et al. Rosiglitazone and delayed onset of proliferative diabetic retinopathy. Arch Ophthalmol 2008;126(6):793-799.


Study Suggests DR Not Responsible for Most Vision Loss in Patients with Diabetes
According to a group of researchers in England, the majority of vision loss among people with diabetes is due to causes other than DR, and best-corrected visual acuity (BCVA) alone is not a reliable criterion for predicting sight-threatening diabetic retinopathy (STDR). For their study, the researchers randomly selected 1,549 people with diabetes mellitus from a national digital photographic screening program. The patients underwent standardized logMAR BCVA measurement and slit lamp biomicroscopy by an experienced ophthalmologist.

Subnormal vision (greater than or equal to 0.3 logMAR) and blindness (greater than 1.3 logMAR) were found in the better-seeing eye of 9.0 percent and 0.45 percent of the patients, respectively. The sensitivity, specificity and positive and negative predictive values of using subnormal vision to screen for STDR in an individual eye were 33.4 percent, 85.9 percent, 18.6 percent and 93.0 percent, respectively. Important contributory causes of moderate vision loss (logMAR 0.50 to 0.98) and of acuity blindness (greater than or equal to 1.0 logMAR) in an individual eye were lenticular opacity (49 percent), including capsular opacification; macular degeneration (29 percent), including myopic degeneration; diabetic maculopathy (15 percent); other media causes (13 percent), including corneal opacity; and amblyopia (10 percent).

Source: Scanlon PH, Foy C, Chen FK. Visual acuity measurement and ocular co-morbidity in diabetic retinopathy screening. Br J Ophthalmol 2008;92(6):775-778.


Effect of Bevacizumab on Inflammation and Proliferation in CNV Membranes
To evaluate the effect of bevacizumab (Avastin, Genentech) on inflammation and proliferation in human choroidal neovascularization (CNV) secondary to age-related macular degeneration, researchers examined CNV membranes extracted from 38 patients. They unexpectedly found that CNV membranes from patients treated with bevacizumab were characterized by significantly high inflammatory and proliferative activity and enhanced endostatin expression.

In the study, 24 patients had received intravitreal bevacizumab one to 154 days before extraction and 14 patients (control group) had received no therapy prior to extraction. CNV membranes were stained for cytokeratin 18, CD68, CD45, intercellular adhesion molecule (ICAM)–1, E-selectin, Ki-67, Thy-1 and endostatin.

The density of macrophages (median 4661.95 cells/mm2), proliferative activity (median 160.19 cells/mm2) and percentage of Thy-1–expressing vessels (median 100 percent) were significantly higher in the bevacizumab group than in the control group (median 882.66 cells/mm2, p<.001; median 34.34 cells/mm2, p<.001; and median 80 percent, p<.001). Endostatin immunoreactivity was considerably stronger in the retina pigment epithelium/Bruch's membrane complex (median 3; range 2-3, p<.001) and stroma (median 3; range 1-3, p<.001) of the bevacizumab group than the control group (median 1.5; range 0-3 and median 1; range, 0-3, respectively). No significant difference was detected in ICAM-1 and E-selectin expression between groups. The density of leukocytes in the bevacizumab group (median, 271.61 cells/mm2) was higher than in the control group (median 116.87 cells/mm2, p=.07), but the difference was not significant.

The authors of the study paper noted that these results should be considered when protocols for combination therapies are established.

Source: Tatar O, Yoeruek E, Szurman P, et al. Effect of bevacizumab on inflammation and proliferation in human choroidal neovascularization. Arch Ophthalmol 2008;126(6):782-790.


Meta-Analysis: Omega-3 Fatty Acid and Fish Intake in the Prevention of AMD
Based on the meta-analysis they conducted, a group of investigators concluded that consumption of fish and foods rich in omega-3 fatty acids may be associated with a lower risk of age-related macular degeneration, but there is insufficient evidence from the current literature to support their routine consumption for AMD prevention.

They systematically searched seven databases with no limits on publication year or language and included randomized controlled trials and prospective cohort, case-control and cross-sectional studies. Of 2,754 abstracts identified, three prospective cohort, three case-control and three cross-sectional studies met the criteria. They quantitatively pooled measures of associations using meta-analytic methods.

Nine studies provided data on a total sample of 88,974 people, including 3,203 AMD cases. A high dietary intake of omega-3 fatty acids was associated with a 38 percent reduction in the risk of late AMD (OR 0.62; 95 percent CI 0.48-0.82). Fish intake at least twice per week was associated with a reduced risk of both early AMD (OR 0.76; 95 percent CI 0.64-0.90) and late AMD (OR 0.67; 95 percent CI 0.53-0.85).

Source: Chong EW, Kreis AJ, Wong TY, et al. Dietary omega-3 fatty acid and fish intake in the primary prevention of age-related macular degeneration: a systematic review and meta-analysis. Arch Ophthalmol 2008;126(6):826-33.


Reduced Contrast Sensitivity Diminishes Quality of Life after Surgery for RD
In a prospective, consecutive, comparative case series, vision-related quality of life (VRQOL) was significantly impaired in patients following surgery to repair rhegmatogenous retinal detachment (RD). In addition, the decreased VRQOL was significantly associated with deterioration of contrast sensitivity. In this case series, 51 RD patients self administered the 25-Item National Eye Institute Visual Function Questionnaire (VFQ-25), as did 46 age-matched normal controls. Among the patients with RD, 33 had undergone pars plana vitrectomy and 18 had been treated with scleral buckling. Investigators measured logMAR BCVA, contrast sensitivity with the CSV-1000E (Vector Vision) and low-contrast acuity with the CSV-1000SLanC (Vector Vision). From the CSV-1000E data they calculated the area under the log contrast sensitivity function (AULCSF).

The VFQ-25 composite score and the subscales associated with near activities, mental health, dependency and peripheral vision were significantly lower in the RD group than in the control group (p<.05). The VFQ-25 composite score significantly correlated with AULCSF (r=0.354; (p<.05) and low-contrast acuity (r=-0.475; (p<0.001). No correlation was found between the VFQ-25 composite score and logMAR BCVA (r=0.172; (p=.229).

Source: Okamoto F, Okamoto Y, Hiraoka T, Oshika T. Vision-related quality of life and visual function after retinal detachment surgery. Am J Ophthalmol 2008;146(1):85-90.


Trial Compares Positions after Macular Hole Surgery
According to the results of a multicenter, prospective, randomized trial, face-down positioning may be preferable to seated positioning following surgery for idiopathic macular hole. Also, the size of the hole appears to be an important factor affecting outcome. The trial involved 150 eyes of 144 patients who were enrolled at two hospitals and randomly separated into two groups. They were instructed to maintain their assigned position for five days after surgery (72 eyes in the seated group and 78 eyes in the face-down group). All patients underwent complete vitrectomy with fluid-air exchange and intraocular gas tamponade.

The overall anatomic success rate of surgery was 92.7 percent. The idiopathic macular holes sealed in 87.5 percent of the seated-position cases and 97.4 percent of the face-down cases (p=.027). Mean visual acuity increased from 0.88 to 0.61 logMAR in the seated group and from 0.84 to 0.60 in the face-down group. However, in a post hoc analysis based on macular hole size, the success rate in holes smaller than 400 µm was not influenced by the postoperative position (p=.47).

Source: Guillaubey A, Malvitte L, Lafontaine PO, et al. Comparison of face-down and seated position after idiopathic macular hole surgery: a randomized clinical trial. Am J Ophthalmol 2008;146(1):128-134.

Table of Contents






NOTEWORTHY: FDA APPROVES TRIAMCINOLONE FORMULATION FOR INTRAVITREAL INJECTION; FDA APPROVES TOPICAL STEROID FOR POSTOP INFLAMMATION AND PAIN; AND OTHER ITEMS OF INTEREST

FDA Approves Triamcinolone Formulation for Intravitreal Injection
The FDA approved Allergan's triamcinolone acetonide injectable suspension (Trivaris 80 mg/mL), a synthetic glucocorticoid corticosteroid with anti-inflammatory action. Delivered via intravitreal injection, Trivaris is indicated for sympathetic ophthalmia, temporal arteritis, uveitis and ocular inflammatory conditions unresponsive to topical corticosteroids.

Full prescribing information is available at www.allergan.com.

Source: Allergan Inc., June 2008.


FDA Approves Topical Steroid for Postop Inflammation and Pain
The FDA approved Sirion Therapeutics' difluprednate ophthalmic emulsion (Durezol 0.05%), a topical steroid for treating postoperative ocular inflammation and pain. Sirion plans to make Durezol commercially available in late 2008.

Two Phase III multicenter studies evaluated the safety and efficacy of placebo compared with Durezol dosed b.i.d. or q.i.d. beginning 24 hours after intraocular surgery. Treatment occurred over four weeks and included tapering. The studies included 438 subjects who presented with significant inflammation as evidenced by an anterior chamber cell grade 2 or higher (greater than 10 cells) the day after surgery. Both dosing regimens had similar overall efficacy in the reduction of anterior chamber cells two weeks following surgery (86 percent for b.i.d. and 87 percent for q.i.d). The q.i.d. regimen had a small numerical advantage in the number of patients who were completely free of inflammation and pain at the one week time point. Based on this numerical advantage and the advantages of treating inflammation aggressively, q.i.d. dosing is recommended.

Durezol was well tolerated. Three percent of subjects in each of the b.i.d. and q.i.d. groups and 1 percent of subjects in the placebo group met the criterion for a clinically significant rise in IOP defined as an observed value of greater than or equal to 21 mmHg and a change from baseline of 10 mmHg. For more information, visit www.siriontherapeutics.com.

Source: Sirion Therapeutics, June 2008.


Three-Month Data on Pharmacokinetics of Fluocinolone Insert Reported
Alimera Sciences reported three-month results from the first human pharmacokinetic study of its fluocinolone-releasing Medidur FA ocular insert for treating patients with diabetic macular edema. This Phase II study is designed to support the ongoing pivotal Phase III clinical trial (Fluocinolone Acetonide in Diabetic Macular Edema, or FAME) of Medidur in DME. It is evaluating the systemic exposure of fluocinolone acetonide after administration of two dose concentrations in 37 patients. Twenty patients received approximately 0.23 µg daily (low dose), and 17 patients received approximately 0.45 µg daily (high dose). Inclusion and exclusion criteria for the study mirror that of the FAME trial.

According to the three-month results, 20 percent of the low-dose patients and 18 percent of the high-dose patients achieved an improvement in best-corrected visual acuity of 15 letters or more from baseline. In addition, both the low dose and the high dose significantly reduced retinal thickness compared with baseline. No adverse events related to IOP were seen in the low-dose patients, while 12 percent of the high-dose patients experienced IOP spikes greater than 30 mmHg. One patient in the high-dose group developed a cataract.

Results will also be reported at six, 12, 18, 24, 30 and 36 months. If approved by the FDA, Alimera plans to market the device under the brand name Iluvien. For more information, visit www.alimerasciences.com.

Source: Alimera Sciences, June 2008.


Enrollment Complete in Pivotal Trials of Corticosteroid-Sparing Agent for Uveitis
Lux Biosciences announced completion of enrollment in the landmark LUMINATE pivotal clinical trial program, which is investigating the use of voclosporin (Luveniq) as a corticosteroid-sparing agent for the treatment of patients with noninfectious uveitis. Luveniq is the oral form of a next-generation calcineurin inhibitor to which Lux Biosciences has an exclusive worldwide license for ophthalmic indications from Isotechnika Inc. of Edmonton, Canada. As planned, the three randomized, placebo-controlled, double-masked studies enrolled approximately 560 patients at 58 sites in seven countries. The company expects to complete the studies before the end of the year.

In the Luveniq Uveitis Multicenter Investigation of a New Approach to TrEatment (LUMINATE) program, Luveniq is being studied using inflammation as an endpoint in both the anterior and posterior segments of the eye. If approved, it would be the first steroid-sparing agent to be commercialized for uveitis in the United States and in most international markets.

Source: Lux Biosciences, June 2008.


Collaboration Aims to Develop Stem/Progenitor Cell-Based Therapies
EyeCyte Inc., an early-stage research and development company focused on the use of stem/progenitor cells in ophthalmology, announced it has secured its Series A funding through an agreement with Pfizer. The financing will fund the company into 2010 and will be primarily used to drive product development of the company's initial clinical target, diabetic retinopathy.

Building on research into retinal disease by Martin Friedlander, MD, PhD, and his laboratory at The Scripps Research Institute, EyeCyte will use the properties of blood and bone marrow-derived progenitor cells to pursue the development of treatments for acquired and inherited retinal diseases. Published and unpublished preclinical data from the Friedlander laboratory demonstrate that specific populations of cells may be therapeutically useful for the treatment of retinal vascular and degenerative diseases. The progenitor cells target sites of retinal ischemia and neovascularization where they stabilize the vasculature in animal models.

Source: EyeCyte Inc., June 2008.


Goal of Research Project is Unique Retinal Laser
Carl Zeiss Meditec reported that it is cooperating with leading scientific institutions to develop a new technology for retinal laser treatments. The concept behind the project, which was selected as the winner of the "Innovation Competition for the Advancement of Medical Technology" by the German Federal Ministry for Education and Research, has already been successfully tested on an experimental basis.

The development effort is aimed at implementing an exact dosage of laser radiation for each individual eye (even for each treatment area within the eye) during retinal procedures by ensuring that the laser automatically adjusts to the optimal temperature needed for a specific treatment. The company said the new laser ensures that treatments are conducted at the lowest temperature required for therapy, largely eliminating side effects and pain.

Source: Carl Zeiss Meditec, June 2008.

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