The Digital Angiography Reading Center (DARC) role in the anecortave acetate clinical trials

Advances in digital camera and computer technology have resulted in imaging systems providing clinically relevant information equivalent to traditional film-based techniques. The Digital Angiography Reading Center (DARC) was created to provide the next generation in reading center assessment for clinical trials of retinal disease. A fully digital angiographic imaging protocol was implemented with the anecortave acetate clinical studies. For image evaluation readers followed a standard manual of definitions and guidelines. Eligibility was determined based on protocol specific criteria. Rapid communication of images between the study sites and DARC permitted screening for eligibility and pre-treatment stratification of all patients prior to enrollment. This screening process was designed to eliminate angiographically ineligible patients from the clinical trials. The result was a reduction in the total number of patients needed to obtain sufficient evaluable patients for statistical assessment of treatment outcome. Digital angiography can be successfully used in clinical trials for retinal disease.     

Preclinical efficacy of anecortave acetate

Anecortave acetate is a unique ocular angiostatic cortisene that has broad-based anti-angiogenic activity in 14 different preclinical models of neovascularization, across multiple species and inducers of neovascularization. Anecortave acetate is being tested clinically for inhibition of choroidal neovascularization associated with age-related macular degeneration.     

Preclinical safety of anecortave acetate

A number of preclinical safety pharmacology and toxicity studies have been performed on the angiostatic cortisene anecortave acetate in various species and using different routes of administration (oral, intravenous, subcutaneous, topical ocular, intraocular injection, posterior juxtascleral) and a wide range of doses (0-1,000 mg/kg). Anecortave acetate did not interact with a broad panel of pharmacological receptors and had no apparent pharmacological effects on major organ systems including the central nervous, gastrointestinal, renal, cardiovascular, and respiratory systems. Oral, topical ocular, and posterior juxtascleral administration of anecortave acetate had no significant ocular or systemic side effects or toxicity. In addition, there was no significant carcinogenic or reproductive/developmental toxicity associated with anecortave acetate in genotoxicity, carcinogenicity, and reproductive toxicity studies.     

Mechanism of action of the angiostatic cortisene anecortave acetate

Anecortave acetate is a unique angiostatic agent. Although derived from the glucocorticoid cortisol acetate, it was designed to be devoid of glucocorticoid activity while retaining efficacious anti-angiogenic activity. These modifications have led to a new class of anti-angiogenic agents, the angiostatic cortisenes. Anecortave acetate has broad based angiostatic activity, inhibiting neovascularization at multiple steps. Unlike several other angiostatic agents that selectively target only one angiogenic factor, anecortave acetate inhibits neovascularization induced by many different angiogenic factors.     

Pharmacokinetics and metabolism of anecortave acetate in animals and humans

The ocular delivery of anecortave acetate was tested in preclinical and clinical pharmacokinetic and metabolism studies. Results of initial studies led to the design of a new cannula that could effectively deliver anecortave acetate as a posterior juxtascleral depot, providing adequate retinal and choroidal drug concentrations for up to 6 months after a single administration. A counter-pressure device was designed to prevent drug reflux during and immediately after posterior juxtascleral depot administration. Pharmacokinetic studies support the effectiveness of these devices. Anecortave acetate is rapidly hydrolyzed by esterases to pharmacologically active anecortave desacetate, and is further reductively metabolized to one major and several minor products that circulate as glucuronide conjugates. Low levels of these anecortave acetate metabolites were detectable for only approximately 2 weeks in the plasma after a 15-mg posterior juxtascleral depot administration to age-related macular degeneration patients. Studies show that posterior juxtascleral depot administration of anecortave acetate is an effective, minimally invasive method of delivering this drug to the choroid and retina.     

First clinical experience with the Alcon LADAR 6000 excimer laser

PURPOSE: To evaluate the reliability and ergonomics and to assess the first clinical results provided by the new LADAR 6000 excimer laser used to correct myopia and astigmatism, both by conventional and wavefront-guided ablation. METHODS: Seventy-four consecutive eyes from 37 patients underwent LASIK as the first field evaluation protocol of the Alcon LADAR 6000 excimer laser. Forty-six eyes were treated by wavefront-guided ablation to correct a manifest spheroequivalent refractive error (MSRE) of -0.50 to -9.75 diopters (D) (mean: -4.19 D, cylinder range: 0.0 to -3.50 D). Twenty-eight eyes were treated by conventional ablation to correct MSRE of -1.00 to -7.00 D (mean: -3.11 D, cylinder range: 0.0 to -1.75 D). Uncorrected (UCVA) and best spectacle-corrected visual acuity (BSCVA), MSRE, and wavefront measurements were assessed. Follow-up was 3 months for all eyes. RESULTS: Three months after surgery, all eyes were within +/- 1.00 D of intended correction. Forty-three (93.5%) eyes treated with wavefront-guided ablation and 25 (89.3%) eyes treated with conventional ablation were within +/- 0.50 D. All eyes reached > or = 20/25 UCVA. UCVA > or = 20/20 was reached in 45 (97.8%) wavefront-guided eyes and 26 (92.9%) conventional eyes; 37 (80.4%) wavefront-guided eyes and 17 (60.7%) conventional eyes had 20/16 UCVA. None of the eyes treated lost > or = 2 lines of BSCVA. CONCLUSIONS: The LADAR 6000 excimer laser results proved to be at least as accurate, predictable, and safe as the results currently achieved with the LADARVision4000 excimer laser. The improved microscope illumination enhances visibility for better consistency and ease of use. The better ergonomics and software design of this platform improved patient flow.     

Inhibition of intraocular tumor growth by topical application of the angiostatic steroid anecortave acetate.

PURPOSE: This study examined the effect of an angiostatic agent on the growth of a highly vascularized intraocular tumor. METHODS: A murine uveal melanoma cell line (99E1) was transplanted intracamerally into athymic nude BALB/c mice. Mice were treated topically three times per day beginning on the day of tumor transplantation and continuing through day 28. Groups included (a) 1% anecortave acetate, (b) vehicle control, or (c) no treatment. Tumor growth was scored clinically according to the volume of anterior chamber occupied by tumor. Intraocular tumor weights were determined on days 10, 14, 21, and 28. The effect of the test agents on tumor cell proliferation was examined in vitro by [3H]thymidine incorporation. RESULTS: Tumors grew progressively in untreated mice and mice treated with the vehicle; tumors filled the entire eye by day 20 and frequently perforated the globe by day 21. By contrast, tumors treated with anecortave acetate grew significantly slower (P < 0.025) and did not perforate the eye. On days 21 and 28 the net tumor weight of the AL-3789-treated animals was 40% to 30% of controls (P < 0.05). Tumor inhibition was presumably due to the angiostatic properties of anecortave acetate because the compound did not affect tumor cell proliferation in vitro. CONCLUSIONS: The topical ocular administration of anecortave acetate restricted the growth of a highly vascularized angiogenic intraocular tumor.     

Posterior juxtascleral injection of anecortave acetate: magnetic resonance and echographic imaging and localization in rabbit eyes

PURPOSE: To confirm juxtascleral delivery of anecortave acetate in rabbit eyes by ocular imaging techniques and to determine drug localization and distribution as a function of time after injection. METHODS: Four female New Zealand white rabbits (weight, 2.5-3.0 kg) received a single juxtascleral posterior sub-Tenon capsule injection of 0.5 mL or 1 mL of 30 mg/mL anecortave acetate. Rabbit eyes were imaged with ultrasonography and magnetic resonance imaging (MRI) before injection, immediately after injection, and at 2 hours, 1 week, and 4 weeks after injection. Rabbit eyes were also imaged with b-mode ultrasonography during the juxtascleral injections. RESULTS: Ultrasonography and MRI demonstrated that juxtascleral posterior sub-Tenon capsule injection of anecortave acetate effectively delivered the drug in direct apposition to the posterior pole of the rabbit eye. The drug remained in the juxtascleral site for at least 5 weeks. The drug was visualized clearly by MRI immediately after injection, decreasing in intensity thereafter. Cannula insertion and the drug delivery process were clearly visualized by real-time ultrasound analysis. Immediately after drug injection, ultrasonography indirectly localized anecortave acetate localization as an echolucent zone posterior to the scleral surface. At the later time points, however, the juxtascleral location of the drug was verified with ultrasonography as a relatively echogenic focus in the same location. CONCLUSIONS: Juxtascleral administration of anecortave acetate via a posterior sub-Tenon capsule approach effectively delivered the drug to the desired position in direct apposition to the globe posteriorly. MRI and ultrasonography both demonstrated that anecortave acetate remained localized to this location for at least 5 weeks after initial injection.     

First experience with amniotic membrane transplantation

BACKGROUND: The purpose of this retrospective study was to analyze the outcome of amniotic membrane transplantation (AMT) performed at the University Eye Clinic Bern during the last 12 months. PATIENTS AND METHODS: Nine men (62.4 +/- 16.7 yrs.) and four women (78.3 +/- 22.3 yrs.) were treated with an AMT and grouped according to the ophthalmologic diagnosis: Group A, chronic corneal surface defect without limbal stem cell deficiency (n = 8); Group B, conjunctival fornix reconstruction (n = 7); Group C, filtering bleb defect (n = 2). RESULTS: 11/17 (65 %) AMT's performed in 14 eyes of 13 patients showed a favorable postoperative result after a mean follow-up time of 8.7 (+/- 2.9) months. In Group A (chronic corneal surface defect) 4/8, in Group B (conjunctival fornix defect) 7/7 and in Group C (filtering bleb defect) 0/2 showed an improvement of the basic ocular problem. 4/8 patients from Group A and 7/7 patients of Group B showed postoperatively a strong reduction of the ocular inflammation. CONCLUSIONS: In the present small study, favorable results were achieved in patients with chronic corneal surface defects without limbal stem cell deficiency and conjunctival fornix defects following AMT. In patients with fornix defects, the AMT seemed to be a valuable alternative to the more complicated transplantation of mouth- or nose mucous membrane. The two eyes with filtering defects failed.     

Continuous-wave diode laserthermokeratoplasty: First clinical experience in blind human eyes

Purpose:To evaluate the safety and stability of laser thermokeratoplasty (LTK) with a continuous-wave diode laser in blind human 'eyes and to optimize parameters for a study in sighted eyes.Setting:Department of Ophthalmology, Medical University Lübeck; GermanyMethods:A continuous-wave diode laser was set to emit radiation with a wavelength of 1.854 μm (Group 1, n = 4) or 1.870 μm (Group 2, n = 4) and 100 to 160 mW power for 10 seconds. A focusing handpiece was coupled with an application mask and fixed by partial vacuum to the conjunctiva or cornea. The radiation was focused into the corneal stroma between 400 and 600 μm in Group 1 and set to 1000 μm in Group 2. Eight (Group 1, single ring) or 16 (Group 2, double ring) coagulations were applied.Results:The refractive change increased with-higher laser, power and smaller ring diameters. Two rings of coagulations provided higher and more stable refractive changes of up to 5.66 diopters (D) than a single ring. The refractive effect stabilized between 3 and 6 months postoperatively. At 1 year, mean, refractive change was +0.99 D ± 0.39 (SD) in Group 1 and +2.32 ± 224 D in Group 2 Extensive endothelial damage occurred in Group 1 but was minimal in Group: 2.Conclusions:Diode LTK was used to treat hyperople safely and effectively Regression occurred mainly in the first 3 postoperative months. With a wavelength of 1.870 μm, corneal endothelial damage was limited.     

First experience with a new echographic contrast agent.

The intravenous injection of an ultrasound contrast agent can enhance signals from blood flow. Broad toxicological and pharmaceutical studies in animals confirmed the safety and efficacy of an ultrasound contrast agent made of microparticles of galactose with stabilised microbubbles in watery suspension (SH U 508 A). In this paper 10 patients with different malignant orbital and ocular tumours have been evaluated with an echo colour Doppler machine before and after the injection of SH U 508 A. An enhancement of the Doppler signals in the lesions in different degrees has been detected. This echographic contrast agent seems to be very important not only in the evaluation of vascular lesions, but also in evaluating the effectiveness of radiotherapy in malignant tumours and could spread the echographic indications in several other ophthalmic fields.     

3 years' clinical experience with IOGEL lenses

A total of 63 IOGEL PC-12 and 12 IOGEL 1103 intraocular lenses have been implanted at Lausanne and Basle University Eye Hospitals, and followed up for up to 3 years. In general, the functional and anatomic results are good. From a comparison of the behavior of IOGEL lenses implanted in the sulcus and capsular bag it is concluded that given a suitable surgical technique the IOGEL 1103 lens with implantation in the capsular bag may be recommended.