Publications by authors named "Michael R Robinson"

60 Publications

Nonclinical Pharmacokinetic and Pharmacodynamic Assessment of Bimatoprost Following a Single Intracameral Injection of Sustained-Release Implants.

Transl Vis Sci Technol 2020 03 20;9(4):20. Epub 2020 Mar 20.

Non-Clinical and Translational Sciences, Allergan plc, Irvine, CA, USA.

Purpose: To assess the pharmacokinetic (PK)/pharmacodynamic (PD) relationship following intracameral Bimatoprost sustained-release (SR) implants (8, 15, 30, and 60 µg) in dogs to determine the optimal investigative dose in humans.

Methods: Forty-four male normotensive beagle dogs were assigned to 1 of 8 groups receiving 8-, 15-, 30-, and 60-µg implants (PD assessment [n = 8/group, 4 groups]; PK assessment [n = 3/group, 4 groups]). Intraocular pressure (IOP) in PD animals and aqueous humor/blood concentrations of bimatoprost and its acid in PK animals were assessed. PK/PD correlation analysis was performed using steady-state data. Residual implants were recovered to assess polymer degradation.

Results: Dose-dependent IOP lowering was observed for all dose groups for at least 3 months postdose. Blood concentrations of bimatoprost and bimatoprost acid were below the limit of quantification (<0.25 ng/mL), whereas dose-dependent concentration-time profiles were observed in the aqueous humor. At steady state, observed and predicted correlation between aqueous humor drug concentration and IOP lowering was similar and translatable to findings in humans following topical bimatoprost eyedrop administration. Implants at all doses were well tolerated and polymer degradation was apparent.

Conclusions: Dose-dependent IOP lowering with Bimatoprost SR was maintained for at least 3 months in dogs, and the implants were well tolerated. The established PK/PD relationship appears to translate to humans. Doses between 8 and 15 µg appear to provide the best benefit/risk profile for clinical development of the implants.

Translational Relevance: The close PK/PD relationship between dog and human helps inform which bimatoprost dose should be investigated in clinical studies.
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http://dx.doi.org/10.1167/tvst.9.4.20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396179PMC
March 2020

Distribution of C-Latanoprost Following a Single Intracameral Administration Versus Repeated Topical Administration.

Ophthalmol Ther 2020 Dec 1;9(4):929-940. Epub 2020 Aug 1.

Allergan, An AbbVie Company, Irvine, CA, USA.

Purpose: To qualitatively evaluate the ocular and periocular distribution of C-latanoprost following a single intracameral administration or repeated topical ocular administration in beagle dogs and cynomolgus monkeys.

Methods: In the dog study, three animals received an intracameral dose of C-latanoprost bilaterally and were euthanized at 1, 2, and 4 h post dose; three control animals received topical C-latanoprost bilaterally once daily for 5 days and were euthanized at 1, 4, and 24 h post final dose. Sagittal 40-µm sections of eyes with surrounding tissues were collected and processed for autoradiography. Methods in the monkey study were similar; two animals received a unilateral intracameral dose of C-latanoprost.

Results: After intracameral dosing in dogs, radioactivity was concentrated in the cornea, iris, ciliary body, and anterior chamber with no radioactivity detected in the eyelids or other periorbital tissues. After topical dosing, radioactivity was distributed in the bulbar conjunctiva, cornea, anterior chamber, iris, ciliary body, upper and lower eyelids, and periorbital tissues (fat/muscle). After intracameral dosing in monkeys, radioactivity was concentrated in the anterior chamber, cornea, iris, ciliary body, and posteriorly along the uveoscleral outflow pathway; there was no radioactivity in the eyelids or periorbital tissues aside from signal in the nasolacrimal duct, likely from reflux of C-latanoprost into the tear film.

Conclusions: Intracameral delivery resulted in more selective target tissue drug exposure. Intracameral drug delivery has potential to reduce ocular surface and periocular adverse effects associated with topical administration of prostaglandin analogues, such as eyelash growth and periorbital fat atrophy.
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http://dx.doi.org/10.1007/s40123-020-00285-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708611PMC
December 2020

Phase 3, Randomized, 20-Month Study of Bimatoprost Implant in Open-Angle Glaucoma and Ocular Hypertension (ARTEMIS 1).

Ophthalmology 2020 12 13;127(12):1627-1641. Epub 2020 Jun 13.

Hamilton Glaucoma Center, Shiley Eye Institute and Viterbi Family Department of Ophthalmology, University of California, San Diego, California.

Purpose: To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of 10- and 15-μg bimatoprost implant in subjects with open-angle glaucoma (OAG) and ocular hypertension (OHT) after initial and repeated administrations.

Design: Randomized, 20-month, multicenter, subject- and efficacy evaluator-masked, parallel-group, phase 3 clinical study.

Participants: Adults with OAG or OHT in each eye, open iridocorneal angle inferiorly in the study eye, and study eye baseline IOP (hour 0; 8 am) of 22-32 mmHg after washout.

Methods: Study eyes received bimatoprost implant 10 μg (n = 198) or 15 μg (n = 198) on day 1 with readministration at weeks 16 and 32, or twice-daily topical timolol maleate 0.5% (n = 198). Intraocular pressure was measured at hours 0 and 2 at each visit.

Main Outcome Measures: Primary end points were IOP and change from baseline IOP through week 12. Safety measures included treatment-emergent adverse events (TEAEs) and corneal endothelial cell density (CECD).

Results: Both dose strengths of bimatoprost implant were noninferior to timolol in IOP lowering after each administration. Mean diurnal IOP was 24.0, 24.2, and 23.9 mmHg at baseline and from 16.5-17.2, 16.5-17.0, and 17.1-17.5 mmHg through week 12 in the 10-μg implant, 15-μg implant, and timolol groups, respectively. The incidence of corneal and inflammatory TEAEs of interest (e.g., corneal endothelial cell loss, iritis) was higher with bimatoprost implant than timolol and highest with the 15-μg dose strength. Incidence of corneal TEAEs increased after repeated treatment; with 3 administrations at fixed 16-week intervals, incidence of ≥20% CECD loss was 10.2% (10-μg implant) and 21.8% (15-μg implant). Mean best-corrected visual acuity (BCVA) was stable; 3 implant-treated subjects with corneal TEAEs had >2-line BCVA loss at their last visit.

Conclusions: Both dose strengths of bimatoprost implant met the primary end point of noninferiority to timolol through week 12. One year after 3 administrations, IOP was controlled in most subjects without additional treatment. The risk-benefit assessment favored the 10-μg implant over the 15-μg implant. Ongoing studies are evaluating other administration regimens to reduce the potential for CECD loss. The bimatoprost implant has potential to improve adherence and reduce treatment burden in glaucoma.
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http://dx.doi.org/10.1016/j.ophtha.2020.06.018DOI Listing
December 2020

Matrix Metalloproteinases and Glaucoma Treatment.

J Ocul Pharmacol Ther 2020 05 1;36(4):208-228. Epub 2020 Apr 1.

Department of Ophthalmology, Duke University, Durham, North Carolina.

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade extracellular matrix (ECM) components such as collagen and have important roles in multiple biological processes, including development and tissue remodeling, both in health and disease. The activity of MMPs is influenced by the expression of MMPs and tissue inhibitors of metalloproteinase (TIMPs). In the eye, MMP-mediated ECM turnover in the juxtacanalicular region of the trabecular meshwork (TM) reduces outflow resistance in the conventional outflow pathway and helps maintain intraocular pressure (IOP) homeostasis. An imbalance in the MMP/TIMP ratio may be involved in the elevated IOP often associated with glaucoma. The prostaglandin analog/prostamide (PGA) class of topical ocular hypotensive medications used in glaucoma treatment reduces IOP by increasing outflow through both conventional and unconventional (uveoscleral) outflow pathways. Evidence from and studies using animal models and anterior segment explant and cell cultures indicates that the mechanism of IOP lowering by PGAs involves increased MMP expression in the TM and ciliary body, leading to tissue remodeling that enhances conventional and unconventional outflow. PGA effects on MMP expression are dependent on the identity and concentration of the PGA. An intracameral sustained-release PGA implant (Bimatoprost SR) in development for glaucoma treatment can reduce IOP for many months after expected intraocular drug bioavailability. We hypothesize that the higher concentrations of bimatoprost achieved in ocular outflow tissues with the implant produce greater MMP upregulation and more extensive, sustained MMP-mediated target tissue remodeling, providing an extended duration of effect.
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http://dx.doi.org/10.1089/jop.2019.0146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232675PMC
May 2020

24-Month Phase I/II Clinical Trial of Bimatoprost Sustained-Release Implant (Bimatoprost SR) in Glaucoma Patients.

Drugs 2020 Feb;80(2):167-179

Allergan plc, Irvine, CA, USA.

Objective: The objective of this study was to evaluate the safety and intraocular pressure (IOP)-lowering effects over 24 months of biodegradable bimatoprost sustained-release implant (Bimatoprost SR) administration versus topical bimatoprost 0.03% in patients with open-angle glaucoma (OAG).

Methods: This was a phase I/II, prospective, 24-month, dose-ranging, paired-eye controlled clinical trial. At baseline following washout, adult patients with OAG (N = 75) received Bimatoprost SR (6, 10, 15, or 20 µg) intracamerally in the study eye; the fellow eye received topical bimatoprost 0.03% once daily. Rescue topical IOP-lowering medication or single repeat administration with implant was permitted. The primary endpoint was IOP change from baseline. Safety measures included adverse events (AEs).

Results: At month 24, mean IOP reduction from baseline was 7.5, 7.3, 7.3, and 8.9 mmHg in eyes treated with Bimatoprost SR 6, 10, 15, and 20 µg, respectively, versus 8.2 mmHg in pooled fellow eyes; 68, 40, and 28% of pooled study eyes had not been rescued/retreated at months 6, 12, and 24, respectively. AEs in study eyes that occurred ≤ 2 days post-procedure typically were transient. After 2 days post-procedure, overall AE incidence was similar between study and fellow eyes, with some events typically associated with topical prostaglandin analogs having lower incidence in study eyes.

Conclusions: Bimatoprost SR showed favorable efficacy and safety profiles up to 24 months, with all evaluated dose strengths demonstrating overall IOP-reducing effects comparable to those of topical bimatoprost. Targeted and sustained delivery of bimatoprost resulted in protracted IOP lowering, suggesting that Bimatoprost SR may represent a transformational new approach to glaucoma therapy. Clinicaltrials.gov identifier: NCT01157364.
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http://dx.doi.org/10.1007/s40265-019-01248-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007425PMC
February 2020

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

J Glaucoma 2019 09;28(9):846-857

Viterbi Family Department of Ophthalmology, Hamilton Glaucoma Center, Shiley Eye Institute, University of California, San Diego, La Jolla, CA.

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.
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http://dx.doi.org/10.1097/IJG.0000000000001307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735525PMC
September 2019

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

Transl Vis Sci Technol 2019 Jan 30;8(1):15. Epub 2019 Jan 30.

Hamilton Glaucoma Center, Shiley Eye Institute and Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA.

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.
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http://dx.doi.org/10.1167/tvst.8.1.15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355114PMC
January 2019

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

J Ocul Pharmacol Ther 2019 04 30;35(3):138-144. Epub 2019 Jan 30.

Allergan plc, Irvine, California.

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.
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http://dx.doi.org/10.1089/jop.2018.0095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6479235PMC
April 2019

Intracameral Sustained-Release Bimatoprost Implant Delivers Bimatoprost to Target Tissues with Reduced Drug Exposure to Off-Target Tissues.

J Ocul Pharmacol Ther 2019 Jan/Feb;35(1):50-57. Epub 2018 Oct 18.

1 Allergan plc, Irvine, California.

Purpose: To explore the ocular distribution of bimatoprost after intracameral administration of a biodegradable sustained-release bimatoprost implant (Bimatoprost SR) versus repeated topical administration of bimatoprost 0.03% ophthalmic solution in dogs. Bimatoprost SR and topical bimatoprost 0.03% previously were shown to have similar intraocular pressure-lowering effects in humans in a phase 1/2 clinical trial.

Methods: Twenty-four beagle dogs received either once-daily topical bimatoprost 0.03% for 7 days or a bilateral intracameral administration of Bimatoprost SR (15 μg). At predetermined time points, ocular tissues were collected and concentrations of bimatoprost and bimatoprost acid were quantified using liquid chromatography-tandem mass spectrometry.

Results: Bimatoprost SR administration enhanced delivery of study drug to a site of action [iris-ciliary body (ICB)] compared with topical bimatoprost (C [bimatoprost+bimatoprost acid] = 18,200 and 4.13 ng/g, respectively). However, distribution of drug to tissues associated with prostaglandin analog (PGA)-related side effects (i.e., bulbar conjunctiva, eyelid margins, and periorbital fat) was limited following Bimatoprost SR administration (C [bimatoprost+bimatoprost acid] = BLQ [beneath the limit of quantitation] to 0.354 ng/g) compared with topical dosing (C [bimatoprost+bimatoprost acid] = 36.6-2,110 ng/g).

Conclusions: Bimatoprost SR administration in dogs selectively delivered drug to the ICB with low or undetectable drug levels in ocular surface and extraocular tissues. Use of Bimatoprost SR for glaucoma treatment may reduce the incidence of adverse events typically associated with topical PGAs by targeting bimatoprost delivery to the key site of action of the PGA class and reducing exposure to off-target tissues.
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http://dx.doi.org/10.1089/jop.2018.0067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354606PMC
July 2020

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

Vet Ophthalmol 2018 Jul 19;21(4):376-381. Epub 2018 Feb 19.

Allergan plc, Irvine, CA, USA.

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.
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http://dx.doi.org/10.1111/vop.12522DOI Listing
July 2018

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

Am J Ophthalmol 2017 Mar 22;175:137-147. Epub 2016 Dec 22.

Allergan plc, Irvine, California.

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.
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http://dx.doi.org/10.1016/j.ajo.2016.11.020DOI Listing
March 2017

Vitreomacular Attachment Ultrastructure and Histopathological Correlation.

Curr Eye Res 2016 08 18;41(8):1098-1104. Epub 2015 Nov 18.

a Department of Ophthalmology , State University of New York, Upstate Medical University , Syracuse , NY , USA.

Purpose: The ultrastructural anatomy of the vitreomacular interface in young human donor eyes and animal eyes is explored using scanning electron microscopy (SEM) to determine its relationship with the formation of the perimacular ridge from abusive head trauma, as well as macular hole formation, vitreomacular traction syndrome, and preretinal hemorrhage.

Materials And Methods: SEM is used to image the posterior poles of 23 human donor eyes, as well as several cow, dog, monkey, pig, and rabbit eyes for vitreomacular interface anatomy. We examined autopsy eyes from abusive head trauma histopathologically.

Results: Two rings of thick, circumferential, vitreous attachment at the area centralis are found. An inner ring at the fovea, R1, and an outer ring at the perifoveal region, R2, are both observed in eyes from donors < 30 years of age; comparatively, in eyes from donors > 30 years, only R2 is present (p<0.001). R2 is found with unique elliptical shape in Cynomolgus monkey. Macula, R1, and R2 are not detected in cow, dog, pig, or rabbit eyes.

Conclusions: The vitreomacular ring attachments found in donor eyes correspond anatomically with the perimacular ridge found histopathologically in abusive head trauma, and likely correlates with the macular hole, vitreomacular traction syndrome, and preretinal hemorrhage. Vitreomacular interface anatomy in the monkey, but not the cow, dog, pig, or rabbit, demonstrates some anatomical similarity to that of the human, consistent with species differences regarding the area centralis.
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http://dx.doi.org/10.3109/02713683.2015.1085578DOI Listing
August 2016

Development of a dexamethasone intravitreal implant for the treatment of noninfectious posterior segment uveitis.

Ann N Y Acad Sci 2015 Nov 22;1358:1-12. Epub 2015 Jul 22.

Allergan, Inc, Irvine, California.

Uveitis is a group of ocular inflammatory disorders that can lead to severe vision loss. Despite advances in anti-inflammatory therapy, many patients are resistant to or intolerant of existing treatments. A biodegradable, sustained-release implant, dexamethasone intravitreal implant 0.7 mg (Ozurdex), has been developed to deliver dexamethasone to target tissues in the posterior segment of the eye, minimizing systemic drug exposure and limiting side effects. The implant releases dexamethasone over a period of up to 6 months as the poly(D,L-lactide-co-glycolide) polymer matrix of the implant is metabolized to carbon dioxide and water. The implant is placed in the vitreous of the eye with a single-use applicator in a sutureless, office-based procedure. Treatment with a single dexamethasone intravitreal implant in patients with noninfectious intermediate or posterior uveitis has been shown to produce significant improvements in intraocular inflammation and best-corrected visual acuity with treatment benefit sustained for 6 months. Dexamethasone intravitreal implant has also been shown to reduce central retinal thickness and improve best-corrected visual acuity in patients with macular edema of various etiologies. The implant has been approved for treatment of noninfectious uveitis involving the posterior segment, diabetic macular edema, and macular edema associated with branch and central retinal vein occlusion.
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http://dx.doi.org/10.1111/nyas.12824DOI Listing
November 2015

Pharmacologic and clinical profile of dexamethasone intravitreal implant.

Expert Rev Clin Pharmacol 2012 Nov;5(6):629-47

Allergan, Inc., 2525 Dupont Drive, Irvine, CA 92612-1531, USA.

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.
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http://dx.doi.org/10.1586/ecp.12.55DOI Listing
November 2012

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

Vet Ophthalmol 2013 Sep 10;16(5):370-6. Epub 2012 Dec 10.

College of Veterinary Medicine, Colorado State University, Fort Collins, CO, USA.

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.
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http://dx.doi.org/10.1111/vop.12011DOI Listing
September 2013

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

Vet Ophthalmol 2013 Mar 22;16(2):163-6. Epub 2012 May 22.

Allergan, Inc. Irvine, CA, USA.

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.
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http://dx.doi.org/10.1111/j.1463-5224.2012.01030.xDOI Listing
March 2013

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

Vet Ophthalmol 2012 Mar 30;15 Suppl 1:71-8. Epub 2011 Nov 30.

College of Veterinary Medicine, Colorado State University, 4408 John F Kennedy Parkway, Apt C202, Fort Collins, CO 80525, USA.

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.
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http://dx.doi.org/10.1111/j.1463-5224.2011.00970.xDOI Listing
March 2012

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

Vet Ophthalmol 2012 Mar 17;15 Suppl 1:60-3. Epub 2011 Oct 17.

College of Veterinary Medicine, Colorado State University, Fort Collins, CO, USA.

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.
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http://dx.doi.org/10.1111/j.1463-5224.2011.00956.xDOI Listing
March 2012

Novel ocular antihypertensive compounds in clinical trials.

Clin Ophthalmol 2011 20;5:667-77. Epub 2011 May 20.

Department of Biological Sciences, Allergan, Inc., 2525 Dupont Dr., Irvine, CA 92612, USA.

Introduction: 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.

Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.2147/OPTH.S15971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3104796PMC
June 2011

Pharmacokinetics of a sustained-release dexamethasone intravitreal implant in vitrectomized and nonvitrectomized eyes.

Invest Ophthalmol Vis Sci 2011 Jun 28;52(7):4605-9. Epub 2011 Jun 28.

Research and Development, Allergan, Inc., Irvine, California 92612, USA.

Purpose: To evaluate dexamethasone pharmacokinetics after implantation of a sustained-release dexamethasone (DEX) intravitreal implant in nonvitrectomized and vitrectomized eyes.

Methods: 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).

Results: 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).

Conclusions: 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.
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http://dx.doi.org/10.1167/iovs.10-6387DOI Listing
June 2011

Treatment of experimental anterior and intermediate uveitis by a dexamethasone intravitreal implant.

Invest Ophthalmol Vis Sci 2011 May 2;52(6):2917-23. Epub 2011 May 2.

Allergan, Inc., Irvine, California 92612, USA.

Purpose: To assess the efficacy of a dexamethasone (DEX) intravitreal implant in a rabbit model of anterior and intermediate uveitis.

Methods: 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.

Results: 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.

Conclusions: A single administration of DEX implant significantly reduced inflammation in an animal model of anterior and intermediate uveitis.
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http://dx.doi.org/10.1167/iovs.10-5939DOI Listing
May 2011

Dexamethasone intravitreal implant for noninfectious intermediate or posterior uveitis.

Arch Ophthalmol 2011 May 10;129(5):545-53. Epub 2011 Jan 10.

Cleveland Clinic Cole Eye Institute, 9500 Euclid Ave, I-32, Cleveland, OH 44195, USA.

Objective: To evaluate the safety and efficacy of 2 doses of dexamethasone intravitreal implant (DEX implant) for treatment of noninfectious intermediate or posterior uveitis.

Methods: 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).

Main Outcome Measure: The main outcome measure was the proportion of eyes with a vitreous haze score of 0 at week 8.

Results: 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).

Conclusions: 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.
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http://dx.doi.org/10.1001/archophthalmol.2010.339DOI Listing
May 2011

Pharmacokinetics and pharmacodynamics of a sustained-release dexamethasone intravitreal implant.

Invest Ophthalmol Vis Sci 2011 Jan 5;52(1):80-6. Epub 2011 Jan 5.

Department of Research and Development, Allergan, Inc., Irvine, CA, USA.

Purpose: To determine the pharmacokinetics and pharmacodynamics of a sustained-release dexamethasone (DEX) intravitreal implant (Ozurdex; Allergan, Inc.).

Methods: 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.

Results: 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).

Conclusions: 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.
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http://dx.doi.org/10.1167/iovs.10-5285DOI Listing
January 2011

Biodegradable implants for sustained drug release in the eye.

Pharm Res 2010 Oct 10;27(10):2043-53. Epub 2010 Jun 10.

Allergan, Inc., 2525 Dupont Dr., Irvine, CA 92612, USA.

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.
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http://dx.doi.org/10.1007/s11095-010-0159-xDOI Listing
October 2010

Evaluation of clearance mechanisms with transscleral drug delivery.

Invest Ophthalmol Vis Sci 2010 Oct 19;51(10):5205-12. Epub 2010 May 19.

Department of Ophthalmology, College of Medicine, Soonchunhyang University, Seoul, South Korea.

Purpose: The goal of this study was to examine elimination pathways when delivering subconjunctivally administered hydrophilic agents to the retinas of rat eyes.

Methods: 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.

Results: 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.

Conclusions: Conjunctival blood and lymphatic vessel elimination considerably limit transscleral hydrophilic drug delivery to the retina.
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http://dx.doi.org/10.1167/iovs.10-5337DOI Listing
October 2010

Vitreous VEGF clearance is increased after vitrectomy.

Invest Ophthalmol Vis Sci 2010 Apr 17;51(4):2135-8. Epub 2009 Dec 17.

Department of Biomedical Engineering, University of Southern California, Los Angeles, California, USA.

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.
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http://dx.doi.org/10.1167/iovs.09-3582DOI Listing
April 2010

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

Curr Opin Ophthalmol 2009 Nov;20(6):511-9

Department of Biomedical Engineering, University of Southern California, Los Angeles, USA.

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.
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http://dx.doi.org/10.1097/ICU.0b013e328330ccb9DOI Listing
November 2009

Novel drug delivery systems for retinal diseases. A review.

Ophthalmic Res 2009 26;41(3):124-35. Epub 2009 Mar 26.

Department of Biomedical Engineering, University of Southern California, Los Angeles, Calif, USA.

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.
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http://dx.doi.org/10.1159/000209665DOI Listing
May 2009

Transport barriers in transscleral drug delivery for retinal diseases.

Ophthalmic Res 2007 12;39(5):244-54. Epub 2007 Sep 12.

Department of Chemical and Biomolecular Engineering, University of Maryland, College Park, MD 20892-5766, USA.

Transscleral delivery has emerged as an attractive method for treating retinal disorders because it offers localized delivery of drugs as a less invasive method compared to intravitreal administration. Numerous novel transscleral drug delivery systems ranging from microparticles to implants have been reported. However, transscleral delivery is currently not as clinically effective as intravitreal delivery in the treatment of retinal diseases. Transscleral drug delivery systems require drugs to permeate through several layers of ocular tissue (sclera, Bruch's membrane-choroid, retinal pigment epithelium) to reach the neuroretina. As a result, a steep drug concentration gradient from the sclera to the retina is established, and very low concentrations of drug are detected in the retina. This steep gradient is created by the barriers to transport that hinder drug molecules from successfully reaching the retina. A review of the literature reveals 3 types of barriers hindering transscleral drug delivery: static, dynamic and metabolic. While static barriers have been examined in detail, the literature on dynamic and metabolic barriers is lacking. These barriers must be investigated further to gain a more complete understanding of the transport barriers involved in transscleral drug delivery.
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http://dx.doi.org/10.1159/000108117DOI Listing
November 2007