[Show abstract][Hide abstract] ABSTRACT: The aim of this work is to develop a technique to accurately measure the diffusion coefficient of drugs and drug surrogates in the vitreous humor using MRI. Fresh bovine eyes were used for drug diffusion study in the vitreous, and Gd-DTPA was chosen as a drug surrogate/contrast agent to visualize the diffusion process by MRI. Experiments were conducted by injecting 30 μl of the Gd-DTPA with a concentration of 20 mM/l in 0.9% saline in the vitreous of the whole bovine eye. MRI images were acquired at regular intervals for 1.5–2 h, and Gd-DTPA concentration was determined from the MRI signal intensity. At each time point, concentration contours were constructed and a least-squares best fit to the corresponding theoretical contours, based on a cylindrical bolus model, was performed. The best fit at different time points resulted in fairly consistent diffusion coefficient values. With the surrogate injection technique perfected, highly-symmetric distribution of Gd-DTPA was observed, allowing for spherically symmetric mathematical models, with adjustments for ellipticity as needed, for the diffusion coefficient analysis. The analysis yielded an average diffusion coefficient value of (3.040 ± 0.274) × 10−6 cm2/s. The 3-D MRI visualization together with careful symmetric injection of the surrogate/contrast agent has provided a quantitative tool for the accurate measurement of the diffusion coefficient. With symmetric injection and corresponding diffusion theory based on the point-source model with adjustments for nonzero bolus size and asymmetry, strong agreement of theory with experiments has been achieved.
International Journal of Heat and Mass Transfer 03/2014; 70:504–514. · 2.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: The challenge in the treatment of chronic retinal diseases is to deliver effective therapy to the target tissues in the back of the eye while limiting drug exposure in nontarget tissues. Intravitreal placement provides the most targeted drug delivery, but repeated penetration of the globe to deliver intravitreal therapy can pose safety risks. A more effective strategy for the treatment of chronic retinal diseases would be to combine intravitreal placement with sustained drug delivery. The dexamethasone intravitreal (DEX) implant is a biodegradable sustained-release intravitreal drug delivery system that is approved for the treatment of macular edema following branch or central retinal vein occlusion and for noninfectious uveitis affecting the posterior segment of the eye. A single DEX implant has been shown to provide clinical benefits for up to 6 months in eyes with retinal vein occlusion or intermediate or posterior uveitis.
Expert Review of Clinical Pharmacology 11/2012; 5(6):629-47.
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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).
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.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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).
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.
[Show abstract][Hide abstract] ABSTRACT: 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
[Show abstract][Hide abstract] ABSTRACT: To assess the efficacy of a dexamethasone (DEX) intravitreal implant in a rabbit model of anterior and intermediate uveitis.
Experimental anterior and intermediate uveitis was induced by a unilateral intracameral injection of Mycobacterium tuberculosis H37Ra antigen in preimmunized rabbits. Four days after uveitis induction, rabbits received DEX implant or underwent a sham procedure (no implant). Clinical and histopathologic signs of uveitis were assessed for 13 days, and levels of inflammatory markers in the iris/ciliary body were measured after 21 days.
All signs of anterior and intermediate uveitis were reduced by the DEX implant compared with sham procedure. At day 13, mean anterior chamber cell scores ± SD for the DEX implant versus the sham procedure were, respectively, 1.9 ± 1.3 versus 4.0 ± 0.0 (P = 0.04), and mean total histologic inflammatory scores were 3.9 ± 2.5 versus 15.4 ± 6.0 (P = 0.026). Similarly, at day 13, mean vitreous haze severity scores (SD) for the DEX implant versus the sham procedure were, respectively, 0.1 ± 0.2 versus 2.7 ± 1.5 (P = 0.026), and mean vitreous inflammatory cell infiltration scores were 0.0 ± 0.0 versus 1.5 ± 1.3. Treatment with the DEX intravitreal implant also significantly reduced the proinflammatory immune response, as measured by cytokine levels in iris/ciliary body.
A single administration of DEX implant significantly reduced inflammation in an animal model of anterior and intermediate uveitis.
[Show abstract][Hide abstract] ABSTRACT: To evaluate dexamethasone pharmacokinetics after implantation of a sustained-release dexamethasone (DEX) intravitreal implant in nonvitrectomized and vitrectomized eyes.
The right eyes of 25 rabbits underwent vitrectomy; contralateral eyes served as nonvitrectomy controls. The 0.7-mg DEX implant was injected into both eyes, and drug concentrations were determined in the vitreous humor and retina for 31 days (on days 2, 8, 15, 22, and 31).
DEX was present in nonvitrectomized and vitrectomized eyes for at least 31 days. There were no statistically significant differences in DEX concentration between nonvitrectomized and vitrectomized eyes at any time point (P > 0.05). The maximum concentration of DEX in nonvitrectomized versus vitrectomized eyes for vitreous humor was 791 ng/mL (day 22) versus 731 ng/mL (day 22), respectively, and for retina it was 4110 ng/mL (day 15) versus 3670 ng/mL (day 22), respectively. Mean absorption (AUC(0-tlast)) of dexamethasone in nonvitrectomized and vitrectomized eyes was not different for both the vitreous humor (13,600 vs. 15,000 ng/day/mL; P = 0.73) and retina (67,600 vs. 50,200 ng/day/mL; P = 0.47).
The vitreoretinal pharmacokinetic profiles were similar between nonvitrectomized and vitrectomized eyes. These observations are consistent with clinical findings of the DEX implant in patients who have undergone vitrectomy and should reduce concerns about the use of the DEX implant in eyes that have undergone vitrectomy.
[Show abstract][Hide abstract] ABSTRACT: To evaluate the safety and efficacy of 2 doses of dexamethasone intravitreal implant (DEX implant) for treatment of noninfectious intermediate or posterior uveitis.
In this 26-week trial, eyes with noninfectious intermediate or posterior uveitis were randomized to a single treatment with a 0.7-mg DEX implant (n = 77), 0.35-mg DEX implant (n = 76), or sham procedure (n = 76).
The main outcome measure was the proportion of eyes with a vitreous haze score of 0 at week 8.
The proportion of eyes with a vitreous haze score of 0 at week 8 was 47% with the 0.7-mg DEX implant, 36% with the 0.35-mg DEX implant, and 12% with the sham (P < .001); this benefit persisted through week 26. A gain of 15 or more letters from baseline best-corrected visual acuity was seen in significantly more eyes in the DEX implant groups than the sham group at all study visits. The percentage of eyes with intraocular pressure of 25 mm Hg or more peaked at 7.1% for the 0.7-mg DEX implant, 8.7% for the 0.35-mg DEX implant, and 4.2% for the sham (P > .05 at any visit). The incidence of cataract reported in the phakic eyes was 9 of 62 (15%) with the 0.7-mg DEX implant, 6 of 51 (12%) with the 0.35-mg DEX implant, and 4 of 55 (7%) with the sham (P > .05).
In patients with noninfectious intermediate or posterior uveitis, a single DEX implant significantly improved intraocular inflammation and visual acuity persisting for 6 months. Application to Clinical Practice Dexamethasone intravitreal implant may be used safely and effectively for treatment of intermediate and posterior uveitis. Trial Registration clinicaltrials.gov Identifier: NCT00333814.
Archives of ophthalmology 01/2011; 129(5):545-53. · 3.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine the pharmacokinetics and pharmacodynamics of a sustained-release dexamethasone (DEX) intravitreal implant (Ozurdex; Allergan, Inc.).
Thirty-four male monkeys (Macaca fascicularis) received bilateral 0.7-mg DEX implants. Blood, vitreous humor, and retina samples were collected at predetermined intervals up to 270 days after administration. DEX was quantified by liquid chromatography-tandem mass spectrometry, and cytochrome P450 3A8 (CYP3A8) gene expression was analyzed by real-time reverse transcription-polymerase chain reaction.
DEX was detected in the retina and vitreous humor for 6 months, with peak concentrations during the first 2 months. After 6 months, DEX was below the limit of quantitation. The C(max) (T(max)) and AUC for the retina were 1110 ng/g (day 60) and 47,200 ng · d/g, and for the vitreous humor were 213 ng/mL (day 60) and 11,300 ng · d/mL, respectively. The C(max) (T(max)) of DEX in plasma was 1.11 ng/mL (day 60). Compared with the level in the control eyes (no DEX implant), CYP3A8 expression in the retina was upregulated threefold up to 6 months after injection of the implant (0.969 ± 0.0565 vs. 3.07 ± 0.438; P < 0.05 up to 2-month samples).
The in vivo release profile of the DEX implant in an animal eye was similar to the pharmacokinetics achieved with pulse administration of corticosteroids (high initial drug concentration, followed by a prolonged period of low concentration). These results are consistent with those in clinical studies supporting the use of the DEX implant for the extended management of posterior segment diseases.
[Show abstract][Hide abstract] ABSTRACT: Glaucoma is a multifactorial disease characterized by progressive optic nerve injury and visual field defects. Elevated intraocular pressure (IOP) is the most widely recognized risk factor for the onset and progression of open-angle glaucoma, and IOP-lowering medications comprise the primary treatment strategy. IOP elevation in glaucoma is associated with diminished or obstructed aqueous humor outflow. Pharmacotherapy reduces IOP by suppressing aqueous inflow and/or increasing aqueous outflow.
This review focuses on novel non-FDA approved ocular antihypertensive compounds being investigated for IOP reduction in ocular hypertensive and glaucoma patients in active clinical trials within approximately the past 2 years.
The mode of IOP reduction, pharmacology, efficacy, and safety of these new agents were assessed. Relevant drug efficacy and safety trials were identified from searches of various scientific literature databases and clinical trial registries. Compounds with no specified drug class, insufficient background information, reformulations, and fixed-combinations of marketed drugs were not considered.
The investigational agents identified comprise those that act on the same targets of established drug classes approved by the FDA (ie, prostaglandin analogs and β-adrenergic blockers) as well as agents belonging to novel drug classes with unique mechanisms of action. Novel targets and compounds evaluated in clinical trials include an actin polymerization inhibitor (ie, latrunculin), Rho-associated protein kinase inhibitors, adenosine receptor analogs, an angiotensin II type 1 receptor antagonist, cannabinoid receptor agonists, and a serotonin receptor antagonist.
The clinical value of novel compounds for the treatment of glaucoma will depend ultimately on demonstrating favorable efficacy and benefit-to-risk ratios relative to currently approved prostaglandin analogs and β-blockers and/or having complementary modes of action.
[Show abstract][Hide abstract] ABSTRACT: 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.
Pharmaceutical Research 10/2010; 27(10):2043-53. · 4.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The goal of this study was to examine elimination pathways when delivering subconjunctivally administered hydrophilic agents to the retinas of rat eyes.
The distribution of sodium fluorescein released from an episcleral implant was compared in live and postmortem eyes. Elimination of the subconjunctivally administered hydrophilic agent IgG through blood and lymphatic vessels was investigated by immunohistochemistry. Additionally, lymphatic elimination of subconjunctivally injected sodium fluorescein was quantitatively evaluated.
NaFl released from an episcleral implant was successfully delivered to the subretinal space in the postmortem eye but failed to do so in the live eye. Immunohistochemical visualization of the conjunctival tissue demonstrated dense distribution of blood and lymphatic vessels while also confirming the elimination of subconjunctivally administered IgG through these same vessels. The lymphatic elimination rate after injection of 75.6 μg of a hydrophilic agent, sodium fluorescein, into the subconjunctival space was determined to be 105 ng/min between 30 and 60 minutes.
Conjunctival blood and lymphatic vessel elimination considerably limit transscleral hydrophilic drug delivery to the retina.
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
Current opinion in ophthalmology 09/2009; 20(6):511-9. · 2.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
Journal articles were identified from the literature search and reviewed.
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.
Ophthalmic Research 04/2009; 41(3):124-35. · 1.56 Impact Factor