Concentrations of Betaxolol in Ocular Tissues of Patients with Glaucoma and Normal Monkeys after 1 Month of Topical Ocular Administration

Hollo, G.; Whitson, Jess T.; Faulkner, Robert; McCue, Bette A.; Curtis, Michael A.; Wieland, H; Chastain, James E.; Sanders, Mark; DeSantis, Louis; Przydryga, Johan; Dahlin, David C.

doi:10.1167/iovs.05-0945

Cited by 42 publications

(26 citation statements)

References 18 publications

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“…In our single dose study, dorzolamide showed significantly higher delivery (both AUC and C max ) to the vitreous and optic nerve than that of brinzolamide. Optic nerve levels of dorzolamide and brinzolamide were significantly higher than those of the vitreous and posterior retina, which is consistent with a previously published report for betaxolol (Holló et al, 2006). Maurice (2002) suggested that drug entry into the retrobulbar space via the conjunctival pathway contributes toward optic nerve drug delivery.…”

Section: Ocular Pharmacokinetics Of Dorzolamide and Brinzolamidesupporting

confidence: 91%

“…Furthermore, the nipradilol levels in the periocular tissue around the equator region were 8.6-fold higher than those in the periocular tissue near the optic nerve. Furthermore, Holló et al (2006) also showed that after topical application of betaxolol in Cynomolgus monkey, drug levels in the anterior part were significantly higher than those in the posterior part of the back of the eye. Such regional differences in the tissue distribution after topical administration might be because the conjunctiva covers only the anterior part of the globe and makes an intimate contact with the sclera in this region, allowing ready exposure of the drug to the sclera and underlying tissues in the anterior part of the globe.…”

Section: Ocular Pharmacokinetics Of Dorzolamide and Brinzolamidementioning

confidence: 92%

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Ocular Pharmacokinetics of Dorzolamide and Brinzolamide After Single and Multiple Topical Dosing: Implications for Effects on Ocular Blood Flow

Kadam¹,

Jadhav²,

Ogidigben³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Ophthalmic carbonic anhydrase inhibitors have been shown to improve retinal and optic nerve blood flow. However, the relative tissue distributions of commercially available carbonic anhydrase inhibitors to the optic nerve are not known. The objective of this study was to compare the ocular pharmacokinetics and tissue distribution profiles of dorzolamide and brinzolamide after single and multiple topical applications. Pigmented rabbits were treated with single or multiple topical administrations of 30 l of Trusopt (dorzolamide hydrochloride ophthalmic solution, 2%) to one eye and 30 l of Azopt (brinzolamide ophthalmic suspension, 1%) to the other eye. Rabbits were euthanized at 10 predetermined time intervals over a period of 24 h, and ocular tissues and plasma samples were collected. For multiple dosing, rabbits were dosed twice per day with an 8-h interval between two doses, groups of rabbits were euthanized at 7, 14, and 21 days at 1 h after the last dose, and ocular tissues and plasma samples were collected. Drug levels in tissue samples were measured using liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameters (C max , T max , and AUC 0-24 ) were estimated by noncompartmental analysis. After a single dose, dorzolamide delivery (AUC 0-24 ) to the aqueous humor, anterior sclera, posterior sclera, anterior retina, posterior retina, anterior vitreous, and optic nerve was 2-, 7-, 2.6-, 1.4-, 1.9-, 1.2-, and 9-fold higher than those of brinzolamide. C max was 2-to 5-fold higher for dorzolamide than that of brinzolamide in all of the ocular tissue. After multiple dosing, dorzolamide levels in the aqueous humor, sclera, retina, vitreous humor, and optic nerve were higher than those of brinzolamide, but statistical significance was achieved only with aqueous humor, vitreous humor, and optic nerve. Dorzolamide levels in the aqueous humor, anterior vitreous, posterior vitreous, and optic nerve were 1.4-to 3.2-, 2.4-to 2.7-, 2.2-to 4.5-, and 2.4-to 5.2-fold higher than those of brinzolamide. Upon multiple dosing, both drugs accumulated in all of the tissues except the conjunctiva, where the drug levels were lower than those observed with single dosing. No significant differences were found in the AUC values of these two drugs in the cornea and conjunctiva after single and multiple dosing. Drug levels were significantly higher in anterior regions than posterior regions in the sclera, retina, and vitreous for both drugs.

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Section: Ocular Pharmacokinetics Of Dorzolamide and Brinzolamidesupporting

confidence: 91%

Section: Ocular Pharmacokinetics Of Dorzolamide and Brinzolamidementioning

confidence: 92%

Ocular Pharmacokinetics of Dorzolamide and Brinzolamide After Single and Multiple Topical Dosing: Implications for Effects on Ocular Blood Flow

Kadam¹,

Jadhav²,

Ogidigben³

et al. 2011

Drug Metab Dispos

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“…On the other hand, using HPLC and tandem MS, the local tissue absorption and distribution of topical administration of betaxolol in both glaucoma patients and normal monkeys were investigated. A significant dose was observed at the posterior of the eyes, which provided evidence for an efficient delivery of drug 155 …”

Section: Applications Of Proteomic Researchmentioning

confidence: 88%

Application of proteomic technology in eye research: a mini review

Lam

Chun

et al. 2008

Clinical and Experimental Optometry

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Proteomics is a rapidly growing research area for the study of the protein cognate of genomic data. This review gives a brief overview of the modern proteomic technology. In addition to general applications of proteomics, we highlight its contribution to studying the physiology of different ocular tissues. We also summarise the published proteomic literature in the broad context of ophthalmic diseases, such as cataract, agerelated maculopathy, diabetic retinopathy, glaucoma and myopia. The proteomic technology is a useful research tool and it will continue to advance our understanding of a variety of molecular processes in ocular tissues and diseases.

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“…In terms of betaxolol, however, topical application of 25 µg / ml suspension for 28 -30 days to monkeys and human eyes resulted in the local concentration reaching approximately 0.1 to 0.4 µM in retina and optic nerve head, an estimation based on the assumption that betaxolol is evenly distributed throughout the retina (33). If this is the case, the blocking effects of betaxolol to not only NMDA receptors but also Ca 2+ and Na + channels are unlikely to be produced.…”

Section: Discussionmentioning

confidence: 99%

Direct Inhibition of N-Methyl-D-Aspartate (NMDA)-Receptor Function by Antiglaucomatous β-Antagonists

et al. 2008

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Abstract. In the present study, we investigated the direct effects of antiglaucoma drugs (timolol, betaxolol, pilocarpine, and latanoprost) on N-methyl-D-aspartate (NMDA)-receptor function using a Xenopus oocytes expression system and electrophysiological techniques. In oocytes expressing wild-type NMDA (NR1a / NR2A) receptors, timolol and betaxolol significantly inhibited glutamate-evoked currents, whereas less inhibition was obtained with pilocarpine, and latanoprost had few effects. Moreover, the effect of timolol and betaxolol was noncompetitive with respect to glutamate. Mutations that changed Asn616 of the NR1a subunit, a critical residue for Mg 2+ blocking of NMDA receptors, to Arg (N616R) or Gln (N616Q) almost eliminated the inhibitory effects of timolol and betaxolol, as well as the blocking effect of Mg 2+. Experiments were also carried out to examine the protective effects of timolol and betaxolol against death of oocytes expressing NMDA receptors. During incubation of oocytes, especially in Mg 2+ -free medium, cell death was induced by addition of glutamate because of the continuous activation of the NMDA receptors expressed. Timolol and betaxolol significantly improved oocyte viability when they were added during the incubation period. These results suggest that timolol and betaxolol may have an additional role that they directly inhibit NMDA-receptor function, possibly via N616 of the NR1a subunit.

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Concentrations of Betaxolol in Ocular Tissues of Patients with Glaucoma and Normal Monkeys after 1 Month of Topical Ocular Administration

Cited by 42 publications

References 18 publications

Ocular Pharmacokinetics of Dorzolamide and Brinzolamide After Single and Multiple Topical Dosing: Implications for Effects on Ocular Blood Flow

Ocular Pharmacokinetics of Dorzolamide and Brinzolamide After Single and Multiple Topical Dosing: Implications for Effects on Ocular Blood Flow

Application of proteomic technology in eye research: a mini review

Direct Inhibition of N-Methyl-D-Aspartate (NMDA)-Receptor Function by Antiglaucomatous β-Antagonists

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