Corneal Penetration and Ocular Bioavailability of Drugs

Burstein, Neal L.; Anderson, Janet A.

doi:10.1089/jop.1985.1.309

Cited by 80 publications

(44 citation statements)

References 41 publications

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“…Thus far, our data suggest that the mechanism for this IOP lowering response is, at least partly, due to an increase in OF, when a very high dose of 10 À3 M SNP was utilized intracamerally. This intracameral concentration is comparable to what would be expected following topical delivery of 2 mg SNP (43500 lg) assuming 1% corneal penetration 36 and no loss over the 1.5 hours of delivery (30-minute intervals). This high concentration requirement may be due to a low rate of penetration into the target tissues, or decreased concentration of the drug at the target sites due to the diverse biologic roles of nitric oxide and its short half-life (T 1/2 10 minutes at 378C) in living tissues.…”

Section: Discussionsupporting

confidence: 63%

Effect of Nitric Oxide on Anterior Segment Physiology in Monkeys

Heyne¹,

Kiland²,

Kaufman³

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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Citation: Heyne GW, Kiland JA, Kaufman PL, Gabelt BT. Effect of nitric oxide on anterior segment physiology in monkeys. Invest Ophthalmol Vis Sci. 2013;54:5103-5110. DOI: 10.1167/iovs.12-11491 PURPOSE. To determine the effect of the nitric oxide donor, sodium nitroprusside (SNP), and the nitric oxide synthase (NOS) inhibitor, L-nitro-arginine-methylester (L-NAME), on IOP, mean arterial pressure (MAP), pupil diameter (PD), refraction (Rfx), aqueous humor formation (AHF), and outflow facility (OF) in monkeys.METHODS. Monkeys were treated with single or multiple topical treatments of 500 lg SNP or L-NAME to one eye. IOP was determined by Goldmann applanation tonometry, PD with vernier calipers in room light, Rfx by Hartinger coincidence refractometry, AHF by fluorophotometry, and MAP with a blood pressure monitor. OF was determined by two-level constant pressure perfusion following anterior chamber exchange. RESULTS.Following four topical treatments with 500 lg SNP, 30 minutes apart, IOP was significantly decreased from 2 to 6 hours compared with the contralateral control with the maximum IOP reduction of 20% at 3 hours (P < 0.001). PD, Rfx, and AHF were unchanged. Effects on MAP were variable. OF after SNP exchange was significantly increased by 77% (P < 0.05) at 10 À3 M. Topical L-NAME had no effect on IOP, PD, Rfx, or MAP.CONCLUSIONS. Enhancement of nitric oxide concentration at targeted tissues in the anterior segment may be a useful approach for IOP reduction for glaucoma therapy. Additional studies are warranted before conclusions can be made regarding the effect of NOS inhibition on ocular physiology in nonhuman primates.

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Section: Discussionsupporting

confidence: 63%

Effect of Nitric Oxide on Anterior Segment Physiology in Monkeys

Heyne¹,

Kiland²,

Kaufman³

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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“…Considering that the cornea is an avascular tissue, topical administration is a first choice approach for treating diseases of the anterior segment of the eye such as glaucoma and keratitis (33) . In addition, topical application may allow the use of locally high concentrations of active principles, with minor or non-significant side effects (33) .…”

Section: Discussionmentioning

confidence: 99%

“…In addition, topical application may allow the use of locally high concentrations of active principles, with minor or non-significant side effects (33) . The HPMC used for the topical instillations of aqueous SNAC and GSNO solutions in this work is a non-toxic hydrophilic mucoadhesive polymer with film forming properties, commonly used in intraocular sur gery, topical administrations, artificial tears and drug vehicle (34,35) .…”

Section: Discussionmentioning

confidence: 99%

Assessment of ocular surface toxicity after topical instillation of nitric oxide donors

Cariello¹,

Souza²,

Lowen³

et al. 2013

Arq. Bras. Oftalmol.

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Ethic committee from UNIFESP: number 1573/08. ABSTRACTPurpose: To evaluate the ocular surface toxicity of two nitric oxide donors in ex vivo and in vivo animal models: S-nitrosoglutathione (GSNO) and S-nitroso-Nace tylcysteine (SNAC) in a hydroxypropyl methylcellulose (HPMC) matrix at final concentrations 1.0 and 10.0 mM. Methods: Ex vivo GSNO and SNAC toxicities were clinically and histologically ana lyzed using freshly excised pig eyeballs. In vivo experiments were performed with 20 albino rabbits which were randomized into 4 groups (5 animals each): Groups 1 and 2 received instillations of 150 µL of aqueous HPMC solution containing GSNO 1.0 and 10.0 mM, respectively, in one of the eyes; Groups 3 and 4 received instillations of 150 µL of aqueous HPMC solution-containing SNAC 1.0 and 10.0 mM, respectively, in one of the eyes. The contralateral eyes in each group received aqueous HPMC as a control. All animals underwent clinical evaluation on a slit lamp and the eyes were scored according to a modified Draize eye test and were histologically analyzed. Results: Pig eyeballs showed no signs of perforation, erosion, corneal opacity or other gross damage. These findings were confirmed by histological analysis. The re was no difference between control and treated rabbit eyes according to the Draize eye test score in all groups (p>0.05). All formulations showed a mean score under 1 and were classified as "non-irritating". There was no evidence of tissue toxicity in the histological analysis in all animals. Conclusion: Aqueous HPMC solutions containing GSNO and SNAC at concentrations up to 10.0 mM do not induce ocular irritation.

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“…The posterior segment includes the posterior sclera, vitreous, retina, choroid, and optic nerve. Penetration across the cornea is proposed as the primary pathway by which drugs reach the aqueous humor and anterior segment after topical ocular administration, whereas the conjunctiva/ sclera route of drug penetration is important for access to ciliary body and posterior tissues (Maurice and Mishima, 1984;Burstein and Anderson, 1985;Lee and Robinson, 1986;Grass and Robinson, 1988;Chien et al, 1990;Schoenwald, 1993 penetration study of brimonidine in albino rabbits demonstrated that when brimonidine solution was applied within a cylindrical well in contact with the cornea surface, the rank order of tissue brimonidine concentrations was cornea Ͼ iris Ͼ aqueous humor Ͼ ciliary body Ͼ anterior sclera Ͼ conjunctiva Ͼ lens (Chien et al, 1990). The same study showed that when brimonidine was applied onto the conjunctiva, outside of the cylindrical well, the rank order of tissue concentrations was conjunctiva Ͼ cornea Ͼ anterior sclera Ͼ ciliary body Ͼ iris Ͼ aqueous humor Ͼ lens.…”

mentioning

confidence: 99%

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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Corneal Penetration and Ocular Bioavailability of Drugs

Cited by 80 publications

References 41 publications

Effect of Nitric Oxide on Anterior Segment Physiology in Monkeys

Effect of Nitric Oxide on Anterior Segment Physiology in Monkeys

Assessment of ocular surface toxicity after topical instillation of nitric oxide donors

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

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