THE LATEST RESEARCH

The retina of an albino rabbit 24 hours after a 2.5-mg intravitreal injection of bevacizumab (Avastin) as part of a 10-rabbit study (Shahar J, et al.). The vertical streak is a Muller cell. Staining in the rod outer segments is visible at the bottom of the image. Confocal immunohistochemistry showed full-thickness penetration at 24 hours, which was absent at four weeks. (Image courtesy of Robert L. Avery, MD.)

Effects of Intravitreal Bevacizumab
Five recently published studies evaluated intravitreal bevacizumab (Avastin) as treatment for several conditions as well as its effects on human macular function and its level of retinal toxicity and penetration in rabbits.

In a short-term retrospective study (Iturralde D, et al.) of 16 eyes (15 consecutive patients) with macular edema secondary to central retinal vein occlusion, treatment with at least one intravitreal injection (1.25 mg/0.05 mL) of bevacizumab decreased the edema and improved visual acuity. The mean number of injections was 2.8 per eye. Mean central macular thickness was 887 µm at baseline and 372 µm at one month (p<0.001). Mean visual acuity improved from 20/600 at baseline to 20/138 at the last follow-up visit, which was a mean of three months after the first injection (p<0.001). In 14 of the 16 eyes, visual acuity improved, as defined by a halving of the visual angle. No adverse events, including endophthalmitis, clinically evident inflammation, increased intraocular pressure, retinal tears, retinal detachment, or thromboembolic events, occurred.

Nine of the patients in the study had previously received intravitreal injections of triamcinolone, which resulted in no improvement or excessive intraocular pressure.

In another study (Spaide RF, et al.), involving two patients, intravitreal injection of bevacizumab (1.25 mg/0.05 mL) led to regression of neovascularization and resolution of vitreous hemorrhage associated with proliferative diabetic retinopathy. In both patients, the vitreous hemorrhage was extensive enough to preclude panretinal photocoagulation. In both patients, retinal neovacularization regressed at one month, and the vitreous hemorrhage partially resolved at one week and was nearly completely resolved at one month. No adverse events occurred. Improvement in visual acuity was noted within the first week after injection. At one month, one patient improved by two lines, and the other improved by five lines. One patient received a second injection at the one-month follow-up (slight leakage from neovascularization on the nerve), and one patient received a second injection at three months (early signs of reperfusion of retinal neovascularization).

In a third study (Maturi RK, et al.), nine patients treated with intravitreal bevacizumab for neovascular age-related macular degeneration (AMD) underwent multifocal electroretinography (mf-ERG) or Ganzfeld electroretinography (G-ERG) before treatment. The five G-ERG patients were tested at one week after injection. The four mf-ERG patients and four of the five G-ERG patients were tested at one month after injection. All mf-ERG tests showed improvement in macular response at one month. The average improvement in the response density of the central 15 degrees was 35 percent (range 11-65 percent). G-ERG testing showed no significant changes in response, although some variation in amplitude and implicit time was observed at different testing times. Visual acuity improved in the majority of patients, and central subfield thickness as measured by optical coherence tomography decreased from 298 µm to 274 µm.

A fourth study (Manzano RP, et al.), involving 12 New Zealand albino rabbits, tested four concentrations of bevacizumab (500 µg/0.1 mL, 1.0 mg/0.1 mL, 2.5 mg/0.1 mL, and 5.0 mg/0.2 mL). Each concentration was injected intravitreally in one eye of each of three rabbits, and the contralateral eye was injected with 0.1 mL of balanced saline solution. The rabbits were observed for 2 weeks. The rabbits were tested with ERGs at baseline and day 14. Histologic and ERG testing indicated no retinal toxicity, but some inflammatory cells were detected in the vitreous at the 5-mg dose.

In a fifth study (Shahar J, et al.), one eye of 10 albino rabbits was injected intravitreally with 2.5 mg/0.1 mL of bevacizumab and the other eye was injected with 0.1 mL of saline. Bevacizumab was found to be nontoxic. The researchers performed ERG testing at three hours, three days, and one, two and four weeks after injection. They recorded visually evoked potential (VEP) at four weeks. They used confocal immunohistochemistry to determine penetration into the retina. ERG responses in the control and experimental eyes were similar throughout follow-up. Flash VEP responses in the experimental eyes showed normal pattern and amplitude and were not different than those recorded by stimulation of the control eye alone. Full thickness retinal penetration was present at 24 hours and absent at four weeks.

Sources: Iturralde D, Spaide RF, Meyerle CB, et al. Intravitreal bevacizumab (Avastin) treatment of macular edema in central retinal vein occlusion: a short-term study. Retina 2006;26:279-284. Spaide RF, Fisher YF. Intravitreal bevacizumab (Avastin) treatment of proliferative diabetic reinopathy complicated by vitreous hemorrhage. Retina 2006;26:275-278. Maturi RK, Bleau LA, Wilson DL. Electrophysiologic findings after intravitreal bevacizumab (Avastin) treatment. Retina 2006;26(3):270-274. Manzano RP, Peyman GA, Khan P, Kivilcim M. Testing intravitreal toxicity of bevacizumab (Avastin). Retina 2006;26(3):257-261. Shahar J, Avery RL, Heilweil G, et al. Electrophysiologic and retinal penetration studies following intravitreal injection of bevacizumab (Avastin). Retina 2006;26(3):262-269.

Fluocinolone Implant for Uveitis and DME: Three-Year Results
Preliminary three-year results from the clinical trial of the fluocinolone-containing intravitreal implant (Retisert) for chronic non-infectious posterior segment uveitis showed that inflammation was controlled in significantly more implanted eyes than non-implanted eyes, but less controlled than was reported at two years. The findings suggested that some eyes might require replacement of the implant between the two-year and three-year time periods, which is consistent with the implant’s FDA approval for a treatment period of 30 months.

The 278 patients in the multicenter, randomized, dose-masked trial were randomized to receive either a 0.59-mg or 2.1-mg implant in one eye. The data released represent the aggregate of the two doses. The uveitis recurrence rate in non-implanted fellow eyes at three years was 57 percent; the recurrence rate in implanted eyes at three years was 33 percent (p<0.001). The recurrence rate at two years in implanted eyes was 11 percent.

At three years, baseline visual acuity improved by three lines or more in 22 percent of implanted eyes vs. 6 percent of non-implanted fellow eyes. Two percent of implanted eyes required removal of the implant to control intraocular pressure; 92 percent required cataract extraction; and 45 percent required filtration surgery.

Preliminary three-year results from the clinical trial of the fluocinolone implant for diabetic macular edema showed that the implant resolved edema at the center of the macula and improved visual acuity by three or more lines in a significant proportion of eyes.

In the multicenter, randomized, controlled trial, 197 patients were randomized 2:1 to receive either a 0.59-mg implant or standard of care defined as repeat laser or observation. At three years, 58 percent of implanted eyes exhibited no evidence of edema vs. 30 percent of eyes receiving standard care (p<0.001). A greater than one step improvement in diabetic retinopathy score was observed in 13 percent of implanted eyes and 4 percent of standard-of-care eyes (p<0.001).

Twenty-eight percent of implanted eyes gained three or more lines of visual acuity compared with 15 percent of standard-of-care eyes (p<0.05). Among (phakic) implanted eyes, 95 percent required cataract extraction. Twenty-eight percent of implanted eyes required a filtering procedure, and 5 percent required explantation to control intraocular pressure.

More complete results from each study will be presented in May at the annual meeting of the Association for Research in Vision and Ophthalmology.

Source: pSivida Limited, February 2006.

Mouse Study Adds to Understanding of Smoking and AMD
According to the results of a study in mice, cigarette smoke-related oxidants, specifically hydroquinone, may stimulate injury to the choriocapillaris and retinal pigment epithelium (RPE), contributing to the association between smoking and AMD. In the study, exposure to cigarette smoke or hydroquinone resulted in the formation of sub-RPE deposits, thickening of Bruch’s membrane, and accumulation of deposits within Bruch’s membrane.

The mice were fed a high-fat diet for 4.5 months and divided into two groups. The first group was exposed to blue-green light (positive control) or whole cigarette smoke. The second group received a purified diet with hydroquinone (0.8 percent) with low or high fat content for 4.5 months. A third group with no intervention served as a negative control.

Most mice fed a high-fat diet without other oxidant exposure exhibited normal morphology, but those exposed to whole cigarette smoke or hydroquinone exhibited a variable degree of basal laminar deposits and diffusely thickened Bruch’s membrane.

The researchers reported that understanding the molecular mechanisms that cause these changes could lead to protective therapies for smokers and non-smokers. They also pointed out that hydroquinone is a component of air pollution, and the incidence of AMD is increasing in areas with high pollution rates.

Source: Espinosa-Heidmann DG, Suner IJ, Catanuto P, et al. Cigarette smoke-related oxidants and the development of sub-RPE deposits in an experimental animal model of dry AMD. Invest Ophthalmol Vis Sci 2006;47:729-737.

Final Results from Drusen Laser Study Published
As indicated by previously published interim results from the Drusen Laser Study, published final results do not support prophylactic laser treatment for the fellow eye in patients with neovascular age-related maculopathy (ARM). Based on the final results, the researchers who conducted the study also concluded that the role of prophylactic laser in patients with bilateral drusen remains unclear.

In the prospective, interventional, randomized, controlled clinical trial conducted at five hospital centers, patients with neovascular ARM and drusen in the study eye (unilateral group) were randomized to laser treatment or no laser treatment. The eyes of patients with bilateral drusen were randomized to right eye, laser or no laser, and left eye, alternative. Laser treatments comprised 12 argon spots. Best-corrected visual acuity and signs of CNV were monitored for three years.

In the unilateral group, 21 of 73 patients (28.8 percent) treated with laser lost vision compared with 13 of 66 patients (19.7 percent) not treated with laser (p=.214). Among the 91 patients treated with laser, choroidal neovascularization (CNV) incidence was 29.7 percent compared with 17.65 percent of the 85 patients not treated with laser (p=.061). Onset of CNV occurred approximately six months earlier in the patients who were treated with laser (p=.05).

In the bilateral group, six of 72 laser-treated eyes (8.3 percent) lost vision compared with 10 of 72 (13.9 percent) fellow eyes (p=.3877). The incidence of CNV was 11.6 percent among 103 eyes treated with laser compared with 6.8 percent among fellow eyes. No difference in onset of CNV was observed.

Source: Owens SL, Bunce C, Brannon AJ, et al. Prophylactic laser treatment hastens choroidal neovascularization in unilateral age-related maculopathy: final results of the drusen laser study. Am J Ophthalmol 2006;141:276-281.