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David M. Linn, Timothy J. Schuchardt, Laurel M. Sly, Jeffrey E. Burr, Nancy J. Britten, James J. Vrbanac; Ocular Delivery Of A Selective Alpha-7 Nicotinic Agonist To The Rabbit Retina. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3237.
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Nicotine and subtype-selective nicotinic (i.e. alpha7) agonists have been shown to provide neuroprotection against excitotoxicity to mammalian retinal ganglion cells in culture. This suggests that selective alpha7 nicotinic compounds can be potential neuroprotective compounds in such ocular diseases as glaucoma. However, the feasibility of ocular delivery of alpha7 selective compounds to the retina remains to be widely explored. The objective of this work was to determine the pharmacokinetic properties of a selective alpha7 nicotinic agonist following ocular delivery.
Dutch-belted rabbits were instilled with 30 µl of a 0.5% solution of a selective alpha7 agonist in both eyes. The dosage used was determined using an approved tolerability study. Plasma samples and ocular tissue samples were collected at 1, 2, 4 and 8 hours. Three rabbits (six eyes) were used for each time point. Plasma, retina, choroid, vitreous humor, aqueous humor, cornea, ICB, bulbar conjunctiva and sclera were collected and stored at -20° C until analysis. Quantitative analysis of plasma, retina and choroid was by LC-MS-MS, and chromatography and mass spectrometry conditions will be described.
Peak concentrations of the alpha7 selective agonist in plasma (21.1 ng/ml) were found at one hour with an approximate half-life of 4 hours. Peak concentrations of compound in retina (1750 ng/g) were found at 2 hours with less than a 50% decrease in peak concentration values observed at 8 hours. Compound levels in choroid increased steadily over the time-course examined (5060 ng/g @ 8 hours).
Ocular delivery of the selective alpha7 agonist was well-tolerated with no observable irritability at 0.5%. The relatively low levels of compound in plasma suggest a low potential for systemic effects. The levels of compound in the retina are consistent with currently approved drugs for topical delivery. Longer exposure times will have to be examined to determine the exact half-life of compound in the retina. In addition, longer exposure times will have to be examined to determine the peak levels of compound in the choroid. Overall, our study indicates that alpha-7 agonists have significant potential for ocular delivery to the posterior segment for retinal diseases such as glaucoma.
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