Vitreous concentration of topically applied brimonidine tartrate 0.2%

Kent, Alexander R.; Nussdorf, Jonathan D.; David, Robert; Tyson, Farrell; Small, David S.; Fellows, Dan

doi:10.1016/s0161-6420(00)00654-0

Cited by 72 publications

(61 citation statements)

References 8 publications

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“…In humans, vitreous concentrations of brimonidine were recently reported to be greater than 2 nM, with a mean value of 185 nM, after topical ocular administration of 0.2% brimonidine tartrate 2 to 3 times daily for 1 to 2 weeks (Kent et al, 2001). When the vitreous humor concentrations are normalized to the clinical dose of 0.2% brimonidine tartrate, the dose-normalized C max values were 82 and 170 nM for multiple dosing in monkeys and rabbits (Table 1), respectively, and seem to be within the range of human vitreous concentrations.…”

Section: Ocular Distribution Of Brimonidinementioning

confidence: 99%

“…Previous studies have reported the ocular penetration of brimonidine into the anterior portion of rabbit eyes after ocular dosing (Chien et al, 1990;Tang-Liu et al, 1996). Measurable brimonidine levels were recently reported in aqueous humor and vitreous humor of human eyes after topical dosing (Karamanos et al, 1999;Kent et al, 2001).Delivery of ocular drugs to the posterior portion of the eye after topical dosing requires drug penetration through the anterior structural barriers of the cornea, conjunctiva, and sclera (Fig. 2).…”

mentioning

confidence: 97%

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Distribution of Brimonidine into Anterior and Posterior Tissues of Monkey, Rabbit, and Rat Eyes

Acheampong¹,

Shackleton²,

John³

et al. 2002

Drug Metab Dispos

111

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ABSTRACT:The objectives of the study were to evaluate the distribution of brimonidine (␣ 2 -adrenergic agonist) into anterior and posterior ocular tissues. Single or multiple doses of a 0.2 or 0.5% brimonidine tartrate solution were administered to one or both eyes of monkeys or to one eye of rabbits. Brimonidine was administered intraperitoneally to rats. After topical administration, [14 C]brimonidine was rapidly absorbed into the cornea and conjunctiva and distributed throughout the eye. [ 14 C]Radioactivity was higher and cleared more slowly in pigmented tissues (iris/ciliary body, choroid/retina, and optic nerve) than in nonpigmented tissues. Single and multiple dosing led to a similar drug distribution, with higher levels of brimonidine measured in pigmented tissues after multiple dosing. Most of the radioactivity extracted from ocular tissues represented unchanged brimonidine. In the rabbits and the monkey treated in only one eye, levels of radioactivity in the untreated eye were low, consistent with the low systemic levels and rapid drug clearance. Posterior ocular tissue concentrations of radioactivity exceeded systemic blood concentrations. The vitreous humor brimonidine concentrations in monkeys treated topically with 0.2% brimonidine tartrate was 82 ؎ 45 nM. Vitreous levels in rabbits confirmed the penetration of brimonidine to the posterior segment. Similar concentrations of brimonidine (22 to 390 nM) were measured in the vitreous and retina of rats injected intraperitoneally with brimonidine. Both topically applied and systemically administered brimonidine reach the back of the eye at nanomolar concentrations sufficient to activate ␣ 2 -adrenergic receptors. The brimonidine levels achieved at the retina are relevant for neuroprotection models.Brimonidine (AGN 190342 1 ; Fig. 1) is a highly selective ␣ 2 -adrenergic agonist approved for the treatment of open-angle glaucoma. Glaucoma represents a family of ocular diseases characterized by a progressive optic neuropathy and loss of retinal ganglion nerve cells (Adkins and Balfour, 1998). One of the primary risk factors for glaucoma is elevated intraocular pressure. When applied to the eye, brimonidine activates ␣ 2 -adrenergic receptors, resulting in decreased aqueous humor production and increased uveoscleral outflow (Toris et al., 1995). These effects on aqueous humor dynamics lead to a reduction in intraocular pressure.Laboratory studies with brimonidine suggest that activation of ␣ 2 -receptors in the retina and/or optic nerve can promote the survival of retinal ganglion nerve cells (David, 1998). Studies show that intraperitoneal and topical administration of brimonidine promoted retinal ganglion cell survival after calibrated optic nerve compression and ischemia/reperfusion in animal models of neuronal injury Yoles et al., 1999;Donello et al., 2001). Importantly, if the ocular instillation of brimonidine promotes retinal ganglion cell survival in glaucomatous neuropathy, then a new therapeutic approach to glaucoma management may be indicated in ...

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Section: Ocular Distribution Of Brimonidinementioning

confidence: 99%

mentioning

confidence: 97%

Distribution of Brimonidine into Anterior and Posterior Tissues of Monkey, Rabbit, and Rat Eyes

Acheampong¹,

Shackleton²,

John³

et al. 2002

Drug Metab Dispos

111

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“…31 In human clinical trials, brimonidine monotherapy lowered the incidence of visual field progression compared to timolol treated patients (9 vs 30%) in the Low Pressure Glaucoma Study Group 32 over a period of 30 months in patients who were able to tolerate the treatment. In addition, brimonidine administered topically twice a day for 2 weeks prior to vitrectomy achieved 2 nM in the vitreous 33 which was at a sufficient concentration for neuroprotection in previous animal studies. 34 However, the repeated administration of topical agents is associated with side effects and non-compliance and therefore other approaches may have additional value.…”

Section: Pharmacological Neuroprotectionmentioning

confidence: 66%

Protecting retinal ganglion cells

Khatib

Martin

2017

Eye

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Retinal ganglion cell degeneration underlies several conditions which give rise to significant visual compromise, including glaucoma, hereditary optic neuropathies, ischaemic optic neuropathies, and demyelinating disease. In this review, we discuss the emerging strategies for neuroprotection specifically in the context of glaucoma, including pharmacological neuroprotection, mesenchymal stem cells, and gene therapy approaches. We highlight potential pitfalls that need to be considered when developing these strategies and outline future directions, including the prospects for clinical trials.

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“…ERG measurements at all study time-points for the study and control eyes. (0.2%) administered in human eyes resulted in vitreous levels well above that required to activate a2-receptors but were hugely variable at 185 nm ± 500 nm (Kent et al 2001). Furthermore, concentrations were vastly higher in pseudophakic eyes (256 ± 639 nm) and aphakic eyes (164 ± 69 nm) compared with phakic eyes (9.3 ± 8.0 nm), although small number of subjects precluded meaningful statistical comparison.…”

Section: Discussionmentioning

confidence: 98%

Evaluation of extended release brimonidine intravitreal device in normotensive rabbit eyes

Deokule

Baffi

Guo

et al. 2012

Acta Ophthalmologica

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Abstract.Purpose: To evaluate the safety profile of a brimonidine extended release intravitreal implant, in normotensive rabbit eyes.Methods: Devices were made from hollow poly‐l‐lactic acid (PLA) tubes and contained hundred micrograms of brimonidine pamoate. Device was injected intravitreally in one eye of 12 New Zealand pigmented rabbits, whereas other eye was injected with a sham implant in masked fashion. Ocular examination was conducted at baseline and months 1, 3 and 6 including dilated fundus examination and electro‐retinogram (ERG). Four rabbits were sacrificed at each time‐point for retinal histology. ERG data were compared between groups and time‐points using anova.Results: No complications were reported from either eye of any rabbits over a 6‐month period. Photopic A wave was reduced in the control eye at 1 month compared with baseline (p < 0.01). There was no significant difference in other ERG parameters between the groups at different time‐points. Gross retinal histology was normal at all time‐points.Conclusion: Extended release intravitreal brimonidine device was found to be safe and in normotensive rabbit eyes.

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Vitreous concentration of topically applied brimonidine tartrate 0.2%

Cited by 72 publications

References 8 publications

Distribution of Brimonidine into Anterior and Posterior Tissues of Monkey, Rabbit, and Rat Eyes

Distribution of Brimonidine into Anterior and Posterior Tissues of Monkey, Rabbit, and Rat Eyes

Protecting retinal ganglion cells

Evaluation of extended release brimonidine intravitreal device in normotensive rabbit eyes

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