Using a Novel, Subconjunctival, Sustained-Release Mitomycin C Formulation in a Rabbit Model of Filtration Surgery with Gel Stent Implantation.

Purpose: To investigate gel stent implantation with and without intraoperative sustained-release mitomycin C (MMC SR) in a rabbit model for gel stent implantation, and to examine aqueous humor outflow (AHO) postimplantation. Methods: Four groups of rabbits were included. Group 1 was untreated (control). Groups 2, 3, and 4 received the gel stent without MMC, with MMC solution (subconjunctival injection), and with MMC SR (subconjunctival injection), respectively. Intraocular pressure (IOP) and AHO were assessed via tonometry and indocyanine green-based angiography, respectively. The main efficacy measure was change in IOP from baseline. Results: Following gel stent implantation, Groups 2, 3, and 4 maintained ≥20% IOP reduction (response) for a median duration of 1 week, 6.5 weeks, and 30 weeks, respectively. Angiography showed normal aqueous humor drainage (Group 1) beginning at the perilimbal trabecular plexus and continuing posteriorly to episcleral outflow vessels. Following implantation, drainage occurred preferentially and directly into the subconjunctival bleb. Conclusions: Gel stent implantation with MMC SR was most effective in achieving sustained, long-term IOP reduction in the rabbit model, compared with implantation with or without MMC solution. Bleb presence and the postimplantation aqueous angiography results indicated redirection of the AHO to the subconjunctival vasculature and presumed lymphatics, suggesting efficient glaucoma filtration to lower IOP in this model. This rabbit model and aqueous angiography may help refine understanding of the mechanism of action of minimally invasive glaucoma surgeries and ultimately translate to improved surgical devices and procedures for patients with glaucoma.

Pediatric Emergency Provider Sexually Transmitted Infection Screening Practices in Adolescents With Oropharyngeal or Anorectal Chief Complaints.

OBJECTIVES: Sexually transmitted infections (STIs) may present with oropharyngeal or anorectal symptoms. Little is known about the evaluation of adolescents with these complaints in the pediatric emergency department (PED). This study aimed to determine the frequency of and factors associated with STI consideration and testing in this population. METHODS: Retrospective chart review of patients aged 13 to 18 years who presented to an urban PED with oropharyngeal or anorectal chief complaints between June 2014 and May 2015. Sexually transmitted infection consideration was defined as sexual history documentation, documentation of STI in differential diagnosis, and/or diagnostic testing. Multivariate logistic regression models were used to identify factors associated with consideration. RESULTS: Of 767 visits for oropharyngeal (89.4%), anorectal (10.4%), or both complaints, 153 (19.9%) had STI consideration. Of the 35 visits (4.6%) that included gonorrhea and/or chlamydia testing, 12 (34.3%) included testing at the anatomic site of complaint. Of those 12 tests, 50.0% were the incorrect test. Patients with older age (adjusted odds ratio [aOR] = 1.5, 95% confidence interval [CI] = 1.3-1.7), female sex (aOR = 1.6, 95% CI = 1.03-2.5), or anorectal complaints (aOR = 2.4, 95% CI = 1.3-4.3) were more likely to have STI consideration. CONCLUSIONS: In an urban PED, only 20% of visits for adolescents with oropharyngeal or anorectal symptoms included STI consideration. Testing was performed in only 5% of cases and often at an inappropriate anatomic site or with the incorrect test. Interventions to increase awareness of appropriate STI consideration and testing for individuals presenting with possible extragenital complaints may help reduce STIs among adolescents.

Episcleral Venous Pressure and the Ocular Hypotensive Effects of Topical and Intracameral Prostaglandin Analogs.

There is a limit beyond which increasing either the concentration of a prostaglandin analog (PGA) or its dosing frequency fails to produce increases in ocular hypotensive efficacy with topical dosing. Intracameral PGA dosing with a bimatoprost implant, however, does not exhibit the same intraocular pressure (IOP)-lowering plateau at studied concentrations, and the maximum-achievable ocular hypotensive effects are not yet known. This suggests that the bimatoprost intracameral implant may activate another mechanism of action in addition to the mechanism(s) activated by topical application. Episcleral venous pressure (EVP) is a key determinant of IOP, and experimental manipulation of the episcleral vasculature can change both EVP and IOP. The recent observation that topical and intracameral PGA drug delivery routes produce different patterns of conjunctival hyperemia suggested that the differences in the IOP-lowering profiles may be caused by differing effects on the episcleral vasculature. Recent experiments in animals have shown that topical PGAs increase EVP, while the bimatoprost intracameral implant causes a smaller, transient increase in EVP, followed by a sustained decrease. The increase in EVP could be limiting the IOP-lowering efficacy of topical PGAs. In contrast, the decrease in EVP associated with the bimatoprost implant could explain its enhanced IOP-lowering effects. Further research on EVP as a target for IOP lowering is indicated to improve our understanding of this potentially important pathway for treating patients with glaucoma.

Intraocular Pressure Effects and Mechanism of Action of Topical Versus Sustained-Release Bimatoprost.

PURPOSE: To assess the intraocular pressure (IOP)-lowering effects of bimatoprost sustained-release implant (BimSR) in normotensive monkeys receiving topical bimatoprost. METHODS: Six eyes from six female, normotensive, cynomolgus monkeys were treated with once-daily topical latanoprost 0.005% plus twice-daily fixed-combination dorzolamide 2%/timolol 0.5%. At week 5, topical latanoprost was switched to once-daily topical bimatoprost 0.03% and twice-daily dorzolamide 2%/timolol 0.5% was continued. At week 8, BimSR 20 µg was administered intracamerally to three eyes and topical therapy was continued in all eyes. At week 12, all topical therapy was discontinued and animals were monitored for another 4 weeks. IOP was measured with a TonoVet rebound tonometer in nonsedated animals weekly for 16 weeks. RESULTS: Average mean (standard deviation) IOP was 19.8 (1.6) mm Hg at baseline, 15.7 (0.9) mm Hg during treatment with topical latanoprost/dorzolamide/timolol from weeks 1 to 5, and 14.2 (0.5) mm Hg during weeks 6 to 8 after topical latanoprost was switched to topical bimatoprost. After BimSR was added, average mean IOP during weeks 9 to 12 was 10.8 (1.3) mm Hg, a decrease of 3.9 mm Hg compared with the topical-only arm. When topical therapy was discontinued, IOP in BimSR-treated eyes remained below that in unmedicated eyes (15.8 [0.9] vs. 20.2 [0.2] mm Hg at weeks 14-16). CONCLUSIONS: Intracameral BimSR has IOP-lowering effects additive to those of topical bimatoprost, suggesting an additional mechanism of action with intracameral drug delivery. TRANSLATIONAL RELEVANCE: Compared with topical bimatoprost, intracameral BimSR may have an additional mechanism of action of IOP lowering.

Dose-Response of Intracameral Bimatoprost Sustained-Release Implant and Topical Bimatoprost in Lowering Intraocular Pressure.

PURPOSE: To compare the dose-response profiles of bimatoprost sustained-release implant (Bimatoprost SR) and topical bimatoprost in lowering intraocular pressure (IOP) in normotensive beagle dogs. METHODS: In 1 study, topical bimatoprost 0.001%, 0.01%, or 0.1% was administered twice daily in the study eye for 5 days. IOP was measured at baseline and up to hour 6 each day. Other studies evaluated the IOP response to a single administration of Bimatoprost SR at dose strengths ranging from 8 to 120 µg. IOP was measured before implant administration and during 3 months of follow-up; IOP in response to topical bimatoprost 0.03% was measured prestudy as an internal control. RESULTS: Mean percentage decrease in IOP from baseline at hour 6 (peak effect) across study days was 15.7%, 36.1%, and 24.8% (2.8, 7.0, and 4.0 mmHg) in animals treated with topical bimatoprost 0.001%, 0.01%, and 0.1%, respectively. After Bimatoprost SR administration, mean percentage decrease in IOP from baseline across 3 months consistently increased with increasing dose strength and was 38.7% (7.2 mmHg) with Bimatoprost SR 120 µg. Mean percentage IOP decrease with topical bimatoprost 0.03% was 27.6% (5.9 mmHg). CONCLUSIONS: Topical bimatoprost demonstrated a U-shaped dose-response curve; increasing the bimatoprost concentration to 0.1% resulted in reduced IOP-lowering efficacy. In contrast, the dose-response curve for Bimatoprost SR showed consistently greater IOP lowering as the dose strength increased, with the dose strength producing maximum IOP lowering not yet determined. At 60- and 120-µg dose strengths, Bimatoprost SR produced greater IOP reductions than were achieved with topical dosing.

Oligonucleotide Array and VITEK Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry in Species Identification of Blood Yeast Isolates.

We evaluated matrix-assisted laser desorption ionization time-of-flight mass spectrometry using VITEK MS (IVD database) and an oligonucleotide array based on the internal transcribed spacer-1 (ITS-1) and ITS-2 sequences of rRNA genes for the identification of Candida spp. from blood cultures. Five-hundred and twelve consecutive bloodstream yeast isolates were collected daily and initially identified by the phenotypic automated method (VITEK YBC or VITEK2 YST card). Inconsistent results were confirmed by D1-D2 region of 28S rRNA genes and ITSs. Excluding two unidentified yeast isolates, the oligonucleotide array and VITEK MS correctly identified 99.6% (508) and 96.9% (494) of 510 yeast isolates, respectively. The oligonucleotide array and VITEK MS demonstrated high correct identification rates for four major Candida species (C. albicans 100%, 98.4%; C. glabrata 100%, 100%; C. parapsilosis 100%, 93.3%; C. tropicalis 100%, 97.3%), but lower correct identification rates for other Candida species (91.7 and 87.5%, respectively). In conclusion, the identification performance of the oligonucleotide array is comparable to that of VITEK MS, and can serve as a supplemental tool for the identification of Candida species.

Bimatoprost sustained-release intracameral implant reduces episcleral venous pressure in dogs.

OBJECTIVE: To determine the effect of a bimatoprost sustained-release intracameral implant (Bimatoprost SR) on episcleral venous pressure (EVP) in normal dogs. METHODS: Normotensive beagle dogs were randomized to receive Bimatoprost SR 30 µg (n = 7) or sham injection (needle insertion only, n = 7) in one eye on day 1. EVP was measured with an episcleral venomanometer through day 65. Episcleral aqueous outflow vessels were identified using fluorescence imaging following intracameral injection of indocyanine green in one additional animal. A separate cohort of dogs that had been trained for conscious intraocular pressure (IOP) measurements received Bimatoprost SR 30 µg (n = 8) in one eye; IOP was evaluated through day 66. RESULTS: Baseline mean EVP was 10.0 mmHg in the Bimatoprost SR group and 10.4 mmHg in the sham group. Eyes treated with Bimatoprost SR exhibited a transient increase in mean EVP that peaked at day 8, followed by a decrease to levels below baseline. From day 29 to day 65, the change in mean EVP from baseline ranged from -2.4 to -3.9 mmHg (P < 0.05 vs. sham). Baseline mean IOP in eyes treated with Bimatoprost SR was 14.9 mmHg, and a steady IOP reduction was maintained through day 66. Bimatoprost SR-treated eyes exhibited a selective, sustained dilation of aqueous outflow vessels that was not observed in sham-treated eyes. CONCLUSIONS: In normal dogs, Bimatoprost SR was associated with a transient increase in EVP followed by a sustained decrease. Changes in EVP were accompanied by a sustained dilation of aqueous outflow vessels.

Pathogen Survey of Pulp and Paper Mill Biosolids Compared with Soils, Composts, and Sewage Biosolids.

Regulatory policies to manage land application of organic materials are risk based, with focus on the quality of these residuals. The Ontario Ministry of the Environment and Climate Change (MOECC) determined that limited information was available on pulp and paper biosolids (PPB) with respect to human enteric pathogens. To address this data gap, MOECC conducted an extensive survey (2005-2006) across Ontario to characterize the microbiological quality of PPB. Quantitative testing was performed for fecal indicators (, enterococci, ) and enteric pathogens (, , , and ) using matrix-validated methods. Comparative benchmark materials (soils and soil amendments) were analyzed concurrently for risk comparison. Results showed that detection rates in PPB were low, 5 to 25% for pathogens and <55% for . , and were found at low frequency (6-8% of samples) and at low mean concentrations (2 most probable number g dry wt., 9 oocysts g dry wt., and 7 cells g dry wt., respectively). was more frequently observed (19% of samples), with a mean of 30 cysts g dry wt. Pathogen concentrations in PPB were generally equivalent to or higher than those in soils, composts, and pelletized sewage biosolids but significantly lower than in sewage biosolids. levels exceeded standards (1000 colony-forming units g dry wt.) in one-third of samples, most often in fresh PPB rather than stored and lagoon solids. Microbial quality of PPB across all surveyed mills tended to be variable and sector- and/or site-specific but in many cases would not consistently meet Canadian federal fertilizers standards. These findings were important to inform Ontario's nutrient management regulations, supporting classification of PPB as higher pathogen risk than compost and commercial fertilizers.

Bimatoprost Sustained-Release Implants for Glaucoma Therapy: 6-Month Results From a Phase I/II Clinical Trial.

PURPOSE: To evaluate the safety and intraocular pressure (IOP)-lowering effect of a biodegradable bimatoprost sustained-release implant (Bimatoprost SR). DESIGN: Phase I/II, prospective, 24-month, dose-ranging, paired-eye controlled clinical trial. METHODS: At baseline following washout, open-angle glaucoma patients (n = 75) were administered Bimatoprost SR (6 µg, 10 µg, 15 µg, or 20 µg) intracamerally in the study eye; the fellow eye began topical bimatoprost 0.03% once daily. Rescue topical IOP-lowering medication or a single repeat treatment with implant was allowed. The primary endpoint was IOP change from baseline. The main safety measure was adverse events. Results through month 6 are reported. RESULTS: Bimatoprost SR provided rapid, sustained IOP lowering. Overall mean IOP reduction from baseline through week 16 in study eyes was 7.2, 7.4, 8.1, and 9.5 mm Hg with the 6-µg, 10-µg, 15-µg, and 20-µg dose strengths of implant, respectively, vs 8.4 mm Hg in topical bimatoprost-treated pooled fellow eyes (data censored at rescue/retreatment). Rescue/retreatment was not required in 91% and 71% of study eyes up to week 16 and month 6, respectively. Adverse events in study eyes usually occurred within 2 days after the injection procedure and were transient. Conjunctival hyperemia with onset later than 2 days after the injection procedure was more common with topical bimatoprost than Bimatoprost SR (17.3% vs 6.7% of eyes). CONCLUSIONS: Bimatoprost SR demonstrated favorable efficacy and safety through 6 months. All dose strengths were comparable to topical bimatoprost in overall IOP reduction through week 16. A single administration controlled IOP in the majority of patients for up to 6 months.

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.

The effect of topical latanoprost on anterior segment anatomic relationships in normal dogs.

OBJECTIVE: Topical latanoprost 0.005% is commonly used in dogs with primary angle closure glaucoma (PACG), and marked miosis has been reported in the literature. To further explore the effect of topical latanoprost on anterior segment anatomy, we performed iridocorneal angle biometrics in normal beagle dogs. METHODS: Thirty-five normal female beagle dogs were assessed using anterior segment optical coherence tomography (AS-OCT). One eye of each dog was scanned with the AS-OCT in the superotemporal quadrant. One drop of latanoprost 0.005% was applied topically, and the OCT scan was repeated 30 min later. Images were imported into ImageJ, and pupil diameter, anterior chamber angle, angle opening distance, angle recess area (ARA), anterior chamber hemifield, and anterior chamber depth were measured. RESULTS: A single drop of latanoprost resulted in marked miosis, anterior bowing of the peripheral iris, narrowing of the iridocorneal angle, and shallowing of the anterior chamber. The anterior segment parameters demonstrated a significant reduction (P-value ≤ 0.001) from baseline following latanoprost with the exception of the ARA (P = 0.07). CONCLUSIONS: Latanoprost significantly decreases pupil diameter and narrows the iridocorneal angle in normal female beagle dogs. Therefore, the utility of latanoprost as a prophylactic treatment for PACG in fellow eyes may be limited. Studies using quantitative iridocorneal angle measurements in goniodysgenic dogs are warranted to understand the changes in iridocorneal angle morphology that occur in PACG in response to topical application of latanoprost.

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.

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 EVP's 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.

Biodegradable implants for sustained drug release in the eye.

The 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.

Vitreous VEGF clearance is increased after vitrectomy.

Purpose. Pars plana vitrectomy (PPV) has been reported to reduce macular thickness and improve visual acuity in patients with diabetic macular edema (ME). The hypothesis for the study was that after PPV, clearance is accelerated and VEGF concentrations are reduced. To test this hypothesis, hVEGF(165) injections were performed in rabbit eyes, with and without PPV, and vitreous VEGF levels were measured as a function of time. Methods. The PPV group rabbits had a bilateral 25-gauge PPV, and in the no-PPV group, rabbits had intact vitreous. Intravitreal injections of hVEGF(165) were performed, and the animals were euthanatized at time points up to 7 days. The vitreous was isolated and an enzyme-linked immunosorbent assay was used to measure the VEGF levels. Pharmacokinetic parameters were determined in a noncompartmental analysis approach. Results. Mean vitreous VEGF levels decreased more rapidly in eyes subjected to PPV than in no-PPV eyes. The vitreous VEGF half-life (t([)(1/2)(])) in PPV eyes was 10 times shorter than that in normal eyes. In addition, mean clearance and mean area under the curve (AUC) increased and decreased, respectively, in eyes that underwent PPV. Conclusions. VEGF clearance is increased after PPV. Reducing VEGF concentrations in the vitreous post-PPV may partially explain the improvement in macular thickness in some patients with ME. Unexpectedly, the half-life of VEGF in the vitreous, even in no-PPV eyes, was <3 hours, whereas compounds of similar molecular weight typically have longer vitreous half-lives. The back of the eye may be uniquely adapted with rapid-clearance mechanisms to regulate vitreous VEGF levels. Further study is suggested.

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.

Novel drug delivery systems for retinal diseases. A review.

INTRODUCTION: Retinal diseases, such as macular edema from diabetic retinopathy and neovascular age-related macular degeneration, are important causes of visual impairment. Pharmacologic intervention has been employed, since laser can have limited success with improving vision. Topical eye drops and systemic therapy deliver low drug levels to the retina and the potential for systemic drug absorption and the accompanying side effects are high. As a result, transscleral and intravitreal drug delivery systems have had increasing importance in treating retinal diseases to deliver therapeutic drug concentrations and to limit the systemic drug exposure. Herein, we will review the novel drug delivery approaches for treating diabetic macular edema and neovascular age-related macular degeneration. MATERIAL AND METHODS: A Medline search was performed to identify articles that described novel drug delivery systems for treating diabetic macular edema and neovascular age-related macular degeneration. Our review was limited to intravitreal drug delivery systems that have recently completed phase II/III clinical trials and/or have been approved by the US Food and Drug Administration. RESULTS: Journal articles were identified from the literature search and reviewed. CONCLUSIONS: Local administration of drugs using primarily intravitreal delivery systems is important in treating retinal diseases. Novel drug delivery approaches for treating diabetic macular edema currently are focused on sustained-release corticosteroids. For neovascular age-related macular degeneration, frequent intravitreal injections of anti-vascular endothelial growth factor compounds are the standard of care. Unmet needs in this population are therapies that reduce the treatment burden and improve visual acuity in a greater proportion of patients.

Reading affect in the face and voice: neural correlates of interpreting communicative intent in children and adolescents with autism spectrum disorders.

CONTEXT: Understanding a speaker's communicative intent in everyday interactions is likely to draw on cues such as facial expression and tone of voice. Prior research has shown that individuals with autism spectrum disorders (ASD) show reduced activity in brain regions that respond selectively to the face and voice. However, there is also evidence that activity in key regions can be increased if task demands allow for explicit processing of emotion. OBJECTIVES: To examine the neural circuitry underlying impairments in interpreting communicative intentions in ASD using irony comprehension as a test case, and to determine whether explicit instructions to attend to facial expression and tone of voice will elicit more normative patterns of brain activity. DESIGN, SETTING, AND PARTICIPANTS: Eighteen boys with ASD (aged 7-17 years, full-scale IQ >70) and 18 typically developing (TD) boys underwent functional magnetic resonance imaging at the Ahmanson-Lovelace Brain Mapping Center, University of California, Los Angeles. MAIN OUTCOME MEASURES: Blood oxygenation level-dependent brain activity during the presentation of short scenarios involving irony. Behavioral performance (accuracy and response time) was also recorded. RESULTS: Reduced activity in the medial prefrontal cortex and right superior temporal gyrus was observed in children with ASD relative to TD children during the perception of potentially ironic vs control scenarios. Importantly, a significant group x condition interaction in the medial prefrontal cortex showed that activity was modulated by explicit instructions to attend to facial expression and tone of voice only in the ASD group. Finally, medial prefrontal cortex activity was inversely related to symptom severity in children with ASD such that children with greater social impairment showed less activity in this region. CONCLUSIONS: Explicit instructions to attend to facial expression and tone of voice can elicit increased activity in the medial prefrontal cortex, part of a network important for understanding the intentions of others, in children with ASD. These findings suggest a strategy for future intervention research.

A pharmacokinetic and safety evaluation of an episcleral cyclosporine implant for potential use in high-risk keratoplasty rejection.

PURPOSE: To determine the short and long-term pharmacokinetics and assess the toxicity of a cyclosporine (CsA) episcleral implant for the prevention of high-risk keratoplasty rejection. METHODS: CsA episcleral implants were made with a high (implant A) or low (implant B) release rate, and in vitro release rates were performed. Short-term pharmacokinetics were performed in rabbits using implant B, and the spatial and temporal spread of drug was observed by sampling from multiple corneal and conjunctival sites at 3 and 72 hours. Implant A was used in long-term pharmacokinetic studies in dogs aged more than 1 year. An ocular toxicity study was performed in dogs older than 1 year. RESULTS: A high release rate was observed with both implants over the initial 5 months followed by a steady state release. The cumulative release over the 400-day assay period from implants A and B was 3.8 +/- 0.3 and 2.3 +/- 0.3 mg, respectively. In the short-term pharmacokinetic studies, the cornea had CsA concentrations of 0.15 +/- 0.06, 0.07 +/- 0.02, and 0.05 +/- 0.02 microg/mg at sites centered 8, 13, and 18 mm away from the implant site, respectively. In the long-term pharmacokinetic studies, corneal CsA levels ranged from 0.18 +/- 0.06 to 0.009 +/- 0.004 microg/mg during the 1-year study. There were no signs of ocular toxicity at 1 year. CONCLUSIONS: Episcleral implants are safe and effective at delivering therapeutic CsA levels to the cornea to potentially prevent corneal allograft rejection. The implant can be surgically inserted at the time of penetrating keratoplasties, since the implant achieves therapeutic levels as early as 3 hours.

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.