Susan S. Lee

Biodegradable Implants for Sustained Drug Release in the Eye

ABSTRACTThe safety and effectiveness of systemic and topical medical therapies for ocular disorders are limited due to poor ocular drug uptake, nonspecificity to target tissues, systemic side effects, and poor adherence to therapy. Intravitreal injections can enhance ocular drug delivery, but the need for frequent retreatment and potential injection-related side effects limit the utility of this technique. Sustained-release drug delivery systems have been developed to overcome these limitations; such systems can achieve prolonged therapeutic drug concentrations in ocular target tissues while limiting systemic exposure and side effects and improving patient adherence to therapy. A critical factor in the development of safe and effective drug delivery systems has been the development of biocompatible polymers, which offer the versatility to tailor drug release kinetics for specific drugs and ocular diseases. Ocular implants include nonbiodegradable and biodegradable designs, with the latter offering several advantages. The polymers most commonly used in biodegradable delivery systems are synthetic aliphatic polyesters of the poly-α-hydroxy acid family including polylactic acid, polyglycolic acid, and polylactic-co-glycolic acid. The characteristics of these polymers for medical applications as well as the pharmacological properties, safety, and clinical effectiveness of biodegradable drug implants for the treatment of ocular diseases are reviewed herein.

Tarsal-conjunctival disease associated with Wegener's granulomatosis.

OBJECTIVE To describe the clinical characteristics of tarsal-conjunctival disease in a cohort of patients with Wegeners granulomatosis (WG). DESIGN Retrospective, case-controlled study. PARTICIPANTS The medical records of 82 consecutive WG patients who underwent an eye examination between January 1996 and June 2002 at the National Institutes of Health were reviewed. METHODS Details of the ophthalmic examination, results of medical therapy, and histopathologic analysis results were recorded. Tarsal-conjunctival disease was defined by (1). conjunctival hyperemia and granuloma formation, areas of necrosis, or active fibrovascular changes in the tarsus or conjunctiva, or (2). evidence of inactive fibrovascular scar. The association of tarsal-conjunctival disease with major organ system involvement was assessed using Bayesian methods. MAIN OUTCOME MEASURES The occurrence and clinical characteristics of tarsal-conjunctival disease in a cohort of patients with WG and associations with major organ system involvement. RESULTS Tarsal-conjunctival disease occurred in 13 of 82 patients (16%) with WG examined over a 6.5-year period. The palpebral surface of the upper lid was involved most commonly, showing conjunctival hyperemia in seven patients, granulomatous lesions in three patients, tarsal-conjunctival necrosis in four patients, active fibrovascular proliferation in six patients, and inactive fibrous scar tissue in seven patients. Histopathologic analysis of eyelid biopsy specimens showed granulomatous inflammation, focal necrosis, and areas of occlusive vasculitis in the tarsus and conjunctiva. In reviewing the patterns of organ involvement in patients with and without tarsal-conjunctival disease, the association of subglottic stenosis and nasolacrimal duct obstruction with tarsal-conjunctival disease showed a high probability of clinical significance. CONCLUSIONS Tarsal-conjunctival disease, a previously uncommon finding in patients with WG, was characterized by inflammation of the palpebral conjunctiva and tarsus followed by a fibrovascular proliferation and scar formation. Because of the important association of tarsal-conjunctival disease with subglottic stenosis, which can progress and lead to laryngeal obstruction and respiratory failure, patients with tarsal-conjunctival disease should be referred to an otolaryngologist for evaluation.

Recent advances in drug delivery systems for treating ocular complications of systemic diseases.

Purpose of review To examine recent advances in the development of pharmacological agents and drug delivery systems for the treatment of ocular conditions associated with systemic diseases including diabetic retinopathy, retinal vein occlusion, uveitis, and HIV-related retinitis. Recent findings Corticosteroids, vascular endothelial-derived growth factor antagonists, and anti-inflammatory agents have been investigated for treating ocular conditions associated with systemic diseases. Systemic pharmacotherapy for specifically treating eye diseases is discouraged as side effects may exacerbate preexisting conditions in patients with a debilitating systemic disease. Local therapy with injections into the vitreous has demonstrated varying degrees of efficacy and safety in treating certain ocular diseases; however, its usefulness in some cases can be limited by a short duration of action and the need for frequent readministration. Efforts have been underway to develop more effective drug delivery systems, such as sustained-release drug implants, to overcome these limitations. Summary Pharmacological agents are currently under investigation, and some have been FDA approved, for the treatment of ocular conditions associated with systemic disease. Advances in the development of drug delivery systems for these agents are expected to further improve the efficacy and safety of pharmacotherapy for ocular diseases in the future.

Gender differences in iridocorneal angle morphology: a potential explanation for the female predisposition to primary angle closure glaucoma in dogs.

OBJECTIVE Female dogs have approximately twice the risk of males for developing primary angle closure glaucoma (PACG). The cause of this gender difference is unknown, but one theory proposes that the gender differences in iridocorneal angle morphology are involved in this risk differential. PROCEDURES Fifty beagles (25 males, 25 females) were included into this study and had normal baseline ophthalmic examinations. Normal dogs were selected so as to avoid any potentially confounding influence of goniodysgenesis. Standardized 20-MHz high-resolution ultrasound images of the iridocorneal angle were acquired from one eye of each dog with the scan plane perpendicular to the limbus in the superior temporal quadrant. Images were imported into ImageJ, and the angle opening distance (AOD) and angle recess area (ARA) were measured by a masked observer, and the analysis of variance method was used to compare differences. RESULTS The mean (±SD) AOD was significantly smaller for female dogs (0.847 ± 0.241 mm) vs. male dogs (1.058 ± 0.322 mm) P-value = 0.012. The mean (± SD) ARA tended to be smaller for female dogs (0.584 ± 0.278 mm) vs. male dogs (0.748 ± 0.385 mm), but this difference was not significant (P-value = 0.092). CONCLUSIONS Female dogs have a significantly smaller AOD vs. males. This difference may render the female iridocorneal angle more susceptible to closure and may partially explain the 2:1 female/male predisposition to PACG. Further studies using goniodysgenic dogs are warranted.

Iridocorneal angle measurements in mammalian species: normative data by optical coherence tomography

Objective  Gonioscopy provides limited quantitative information to compare the iridocorneal anatomy across different species. In addition, the anatomic relationships by histologic examination are altered during processing. As a result, the comparative anatomy of the iridocorneal angle across several mammalian species was evaluated by Optical Coherence Tomography (OCT). Methods  Cats, beagle dogs, minipigs, owl monkeys, cynomolgus monkeys, and rhesus monkeys (n = 6 or 7 per species) were evaluated. Imaging was performed using the OCT. The anterior chamber angle (ACA), angle opening distance (AOD), and the angle recess area (ARA) were evaluated. Results  AC angle: cat (63 ± 6°) > owl monkey (54 ± 4°) > beagle dog (42 ± 4°) > minipig (40 ± 3°) > rhesus monkey (36 ± 1°) > cynomolgus monkey (34 ± 2°). AOD: cat (3.3 ± 0.5 mm) > owl monkey (2.05 ± 0.2 mm) > beagle dog (1.08 ± 0.1 mm) > rhesus monkey (0.92 ± 0.06 mm) > minipig (0.64 ± 0.04 mm) > cynomolgus monkey (0.43 ± 0.03 mm). ARA: cat (3.5 ± 0.1 mm(2) ) > owl monkey (1.41 ± 0.2 mm(2) ) > dog (0.88 ± 0.1 mm(2) ) > rhesus monkey (0.62 ± 0.06 mm(2) ) > minipig (0.21 ± 0.05 mm(2) ) > cynomolgus monkey (0.15 ± 0.01 mm(2) ). Conclusions  This study benchmarks the normative iridocorneal angle measurements across different mammalian species by OCT. These data can be useful to compare iridocorneal angle measurements in disease states as OCT evolves as a common diagnostic tool in veterinary ophthalmic research and practice.

Topical application of 0.005% latanoprost increases episcleral venous pressure in normal dogs.

INTRODUCTION Episcleral venous pressure (EVP) has an important role in intraocular pressure (IOP) homeostasis and accounts for more than 70% of the IOP in the normal dog. A frequently used species in glaucoma research is the normotensive dog especially when evaluating the efficacy of prostaglandin analogues and prostamides; however, aqueous humor dynamic studies in normal dogs are lacking, and the effect of 0.005% latanoprost on canine EVP is not known. We sought to determine the effects to the EVP of topically applied 0.005% latanoprost in the normotensive beagle dog. METHODS Female beagle dogs (n = 14) were used and each had a normal ophthalmic examination on study entry. EVP was determined using a standard episcleral venomanometer. Animals were dosed in one eye with 0.005% latanoprost, and the effects on EVP were compared with the averaged baseline EVPs determined in the predosing phase and the fellow nondosed eye. The Mixed Model Repeated Measures method was used to analyze the EVP data. RESULTS During the dosing phase of the study with topical 0.005% latanoprost, the mean EVPs of dosed eyes were significantly higher than that of nondosed eyes (P < 0.0001). CONCLUSIONS The increase in EVP in the dog with exposure to topical 0.005% latanoprost has not been observed in other species that have been studied, such as in the mouse and in humans, where the drug had no significant effect on the EVP. This response may be unique to dogs and suggests that dogs may not fully mimic human aqueous humor dynamics with topical 0.005% latanoprost. Although frequently performed in human studies, EVP should not be regarded to be a constant value in aqueous humor dynamic studies in the normal beagle dog.

Fibrovascular Changes Misdiagnosed as Cytomegalovirus Retinitis Reactivation in a Patient with Immune Recovery

A patient with human immunodeficiency virus infection and cytomegalovirus (CMV) retinitis developed immune recovery uveitis as a result of receipt of highly active antiretroviral therapy. Fibrovascular changes occurred in the CMV retinitis scar, were misdiagnosed as CMV retinitis reactivation, and were treated with anti-CMV medication. Fibrovascular membranes can be misdiagnosed as reactivated CMV retinitis, and a proper diagnosis is essential to avoid unnecessary therapy with potentially toxic antiviral medications.

Advances in Biodegradable Ocular Drug Delivery Systems

The limitations of existing medical therapies for ocular disorders include low drug bioavailability, nonspecificity, side effects, and poor treatment adherence to therapy. These limitations may be overcome through the use of sustained-release intraocular drug delivery systems. Critical to the development of such systems has been the introduction of biocompatible polymers (biodegradable and nonbiodegradable) that allow for drug release kinetics to be tailored for specific drugs and ocular diseases. Drug delivery systems composed of biodegradable polymers, such as polylactic-co-glycolic acid, appear to be particularly well suited for such applications. This review examines the characteristics of these polymers for medical applications, as well as the pharmacological properties, safety, and clinical effectiveness of biodegradable drug implants for the treatment of sight-threatening ocular diseases.

Post-surgical scleritis associated with the ganciclovir implant.

Although the ganciclovir implant is an effective and well-tolerated treatment for cytomegalovirus retinitis in patients with human immunodeficiency virus infection, complications that may occur include retinal detachment, implant extrusion, and endophthalmitis. A 22-year-old woman with human immunodeficiency virus infection presented with a painful left eye with scleritis overlying previous ganciclovir implant sclerotomy sites. The inflammation progressed 360 degrees around the pars plana with progressive thinning at the implant sites. Post-surgical necrotizing scleritis is another complication that can occur in patients with ganciclovir implants.

New corticosteroid-eluting porous polyethylene implant for the management of lower eyelid retraction: a pilot study.

Purpose: Lower eyelid retraction after trauma presents a challenging management problem. We postulated that a porous polyethylene (pPE) eyelid spacer coated with a polyvinyl alcohol (PVA) and triamcinolone acetonide (TA) matrix could deliver corticosteroid locally over extended periods and modulate inflammation and scar formation. We designed a pPE corticosteroid-eluting implant and evaluated its characteristics in vitro and in vivo. Methods: The release characteristics of pPE implants coated with a PVA/TA matrix of low, intermediate, and high doses of TA were studied in vitro. The implants were then placed in the posterior lamella of lower eyelids of Dutch Belted rabbits for 12 weeks. Clinical events were recorded and eyelids were examined for gross and histologic features, including capsular thickness and degree of vascularity, fibrovascular ingrowth, and inflammatory response. Results: In vitro, implants coated with the intermediate and high doses of TA released the drug at a steady rate for at least 78 days. In rabbits, the PVA and PVA/TA coating prevented fibrovascular ingrowth, except where breaks in the PVA/TA coat were present. Implants with PVA/TA coating demonstrated less inflammation and capsule vascularity. An inverse correlation between TA dose and capsule thickness was noted. Conclusions: We describe a novel drug-release pPE eyelid implant. The corticosteroid-eluting implant demonstrated antiangiogenic and anti-inflammatory properties, which could prove beneficial in the treatment of lower eyelid retraction.