Bimatoprost sustained‐release intracameral implant reduces episcleral venous pressure in dogs

Lee, Susan S.; Burke, James A.; Shen, Jie; Almazan, Alexandra; Orilla, W.; Hughes, Patrick M.; Zhang, Jingyan; Li, Huajiang; Struble, Craig B; Miller, Paul E.; Robinson, Michael R.

doi:10.1111/vop.12522

Cited by 33 publications

(45 citation statements)

References 27 publications

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“…A possible explanation is that the intraocular drug levels achieved with intracameral delivery, 102 and the subsequent MMP upregulation in target tissues, far exceed that achieved with topical dosing, and this may overcome the ceiling effect on IOP reduction that is observed with topical dosing. Alternatively, other mechanisms of IOP lowering may be unlocked with intracameral delivery, such as reduction of the episcleral venous pressure, which has been observed with a PGA only with intracameral dosing 107 and not with topical dosing 108 in nonclinical studies. Sustained delivery of bimatoprost to conventional outflow tissues could potentially alter the proportion of high to low flow regions because of increased MMP activation, 109,110 thus increasing total outflow facility.…”

Section: Exploiting Mmps In Glaucoma Therapy: Development Of a Bimatomentioning

confidence: 99%

Matrix Metalloproteinases and Glaucoma Treatment

Weinreb

Robinson

Dibas

et al. 2020

Journal of Ocular Pharmacology and Therapeutics

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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 in vivo and in vitro 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. IOP, intraocular pressure; MMP, matrix metalloproteinase; MT-MMP, membrane-type MMP; TIMP, tissue inhibitor of metalloproteinase.MMPS AND GLAUCOMA TREATMENT 209 210 WEINREB ET AL.

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Section: Exploiting Mmps In Glaucoma Therapy: Development Of a Bimatomentioning

confidence: 99%

Matrix Metalloproteinases and Glaucoma Treatment

Weinreb

Robinson

Dibas

et al. 2020

Journal of Ocular Pharmacology and Therapeutics

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“…Normality of data was assessed with the Shapiro-Wilk test. Differences in pupil diameter (tropicamide, latanoprost) and IOP (latanoprost) between eyes receiving vehicle (control) or albumin (0.4 or 1.5%) were assessed with a mixed model for repeated measures (MMRM) using the R software version 3.6.0 (Lee et al, 2018). In the model, PD or IOP were the response variable, the group (control or albumin), time (0 to 480 min) and group-by-time interaction were treated as fixed effects, and the animal and animal-by-group interaction were treated as random effects, using animal as block.…”

Section: Discussionmentioning

confidence: 99%

Albumin Levels in Tear Film Modulate the Bioavailability of Medically-Relevant Topical Drugs

2020

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The breakdown of blood-tear barrier that occurs with ocular pathology allows for large amounts of albumin to leak into the tear fluid. This process likely represents an important restriction to drug absorption in ophthalmology, as only the unbound drug is transported across the ocular tissue barriers to exert its pharmacologic effect. We aimed to investigate the effects of albumin levels in tears on the bioavailability of two commonly used ophthalmic drugs: tropicamide, an antimuscarinic that produces mydriasis and cycloplegia, and latanoprost, a PGF2a analog used for the treatment of glaucoma. Eight female beagle dogs underwent a randomized, vehicle-controlled crossover trial. For each dog, one eye received 30 µl of artificial tears (control) or canine albumin (0.4 or 1.5%) at random, immediately followed by 30 µl of 1% tropicamide (2 days, 24 h washout) or 0.005% latanoprost (2 days, 72 h washout) in both eyes. Pupil diameter (digital caliper) and intraocular pressure (IOP; rebound tonometry) were recorded at various times following drug administration (0 to 480 min) and compared between both groups with a mixed model for repeated measures. Albumin in tears had a significant impact on pupillary diameter for both tropicamide (P ≤ 0.001) and latanoprost (P ≤ 0.047), with no differences noted between 0.4% and 1.5% concentrations. Reduction in the maximal effect (pupil size) and overall drug exposure (area under the effect time-curve of pupil size over time) were significant for tropicamide (6.2-8.5% on average, P ≤ 0.006) but not for latanoprost (P ≥ 0.663). The IOP, only measured in eyes receiving latanoprost, was not significantly impacted by the addition of either 0.4% (P = 0.242) or 1.5% albumin (P = 0.879). Albumin in tear film, previously shown to leak from the conjunctival vasculature in diseased eyes, may bind to topically administered drugs and reduces their intraocular penetration and bioavailability. Further investigations in clinical patients and other commonly used ophthalmic medications are warranted.

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“…Externally placed devices include the OTX‐TP travoprost punctal plugs (Ocular Therapeutix, Inc) and the Helios™ bimatoprost periocular ring (Allergan plc) for placement into the conjunctival fornix . Intracameral implants include Bimatoprost SR (Allergan), ENV515 travoprost (Envisia Therapeutics, Inc), OTX‐TIC travoprost (Ocular Therapeutix, Inc), and iDose travoprost (Glaukos ® ) . Intracameral, biodegradable latanoprost‐, bimatoprost‐, and travoprost‐releasing devices have been tested successfully in normal dogs and dogs with POAG, but we are not aware of any plans to move these devices into veterinary clinical application .…”

Section: Optimization Of Iop‐lowering Medical Treatmentmentioning

confidence: 99%

“…39,40 Intracameral implants include Bimatoprost SR (Allergan), ENV515 travoprost (Envisia Therapeutics, Inc), OTX-TIC travoprost (Ocular Therapeutix, Inc), and iDose travoprost (Glaukos ® ). 39,41 Intracameral, biodegradable latanoprost-, bimatoprost-, and travoprost-releasing devices have been tested successfully in normal dogs and dogs with POAG, but we are not aware of any plans to move these devices into veterinary clinical application. [41][42][43][44] The use of ocular, slow-releasing drug implants is not new in veterinary ophthalmology since cyclosporine devices are being used in both horses and dogs for recurrent uveitis, immune-mediated keratitis, and keratoconjunctivitis sicca.…”

Section: Lowering Medical Treatmentmentioning

confidence: 99%

“…39,41 Intracameral, biodegradable latanoprost-, bimatoprost-, and travoprost-releasing devices have been tested successfully in normal dogs and dogs with POAG, but we are not aware of any plans to move these devices into veterinary clinical application. [41][42][43][44] The use of ocular, slow-releasing drug implants is not new in veterinary ophthalmology since cyclosporine devices are being used in both horses and dogs for recurrent uveitis, immune-mediated keratitis, and keratoconjunctivitis sicca. [45][46][47] Our discussions on medical management of canine glaucoma also included the evaluation of compounds to decrease the rate of secondary glaucoma following phacoemulsification surgery.…”

Section: Lowering Medical Treatmentmentioning

confidence: 99%

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The future of canine glaucoma therapy

Komàromy

Bras²,

Esson

et al. 2019

Veterinary Ophthalmology

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Canine glaucoma is a group of disorders that are generally associated with increased intraocular pressure (IOP) resulting in a characteristic optic neuropathy. Glaucoma is a leading cause of irreversible vision loss in dogs and may be either primary or secondary. Despite the growing spectrum of medical and surgical therapies, there is no cure, and many affected dogs go blind. Often eyes are enucleated because of painfully high, uncontrollable IOP. While progressive vision loss due to primary glaucoma is considered preventable in some humans, this is mostly not true for dogs. There is an urgent need for more effective, affordable treatment options. Because newly developed glaucoma medications are emerging at a very slow rate and may not be effective in dogs, work toward improving surgical options may be the most rewarding approach in the near term. This Viewpoint Article summarizes the discussions and recommended research strategies of both a Think Tank and a Consortium focused on the development of more effective therapies for canine glaucoma; both were organized and funded by the American College of Veterinary Ophthalmologists Vision for Animals Foundation (ACVO‐VAF). The recommendations consist of (a) better understanding of disease mechanisms, (b) early glaucoma diagnosis and disease staging, (c) optimization of IOP‐lowering medical treatment, (d) new surgical therapies to control IOP, and (e) novel treatment strategies, such as gene and stem cell therapies, neuroprotection, and neuroregeneration. In order to address these needs, increases in research funding specifically focused on canine glaucoma are necessary.

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Bimatoprost sustained‐release intracameral implant reduces episcleral venous pressure in dogs

Abstract: 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.

Cited by 33 publications

References 27 publications

Matrix Metalloproteinases and Glaucoma Treatment

Matrix Metalloproteinases and Glaucoma Treatment

Albumin Levels in Tear Film Modulate the Bioavailability of Medically-Relevant Topical Drugs

The future of canine glaucoma therapy

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