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DF Woodward, C Madhu, RM Burk, SW Andrews, J Chen, AH Krauss, B Brar, ME Garst, DD S Tang-Liu, LA Wheeler; AGN 192024 (Lumigan®): a Synthetic Prostamide Analog that Lowers Primate Intraocular Pressure by Virtue of Its Inherent Pharmacological Activity . Invest. Ophthalmol. Vis. Sci. 2002;43(13):4110.
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Purpose: AGN 192024 (Lumigan) is a synthetic prostamide analog and a potent and highly efficacious ocular hypotensive agent. In addition to intraocular pressure studies, ocular distribution studies were conducted in living monkeys to determine concentrations of bimatoprost in various ocular tissues over a 24 hr time course. Methods: Intraocular pressure (IOP) was measured by pneumatonometry in normal and laser-induced ocular hypertensive monkeys. In bioavailability studies 0.1% [3H-] AGN 192024 was administered bilaterally to cynomolgus monkeys and one animal was euthanized at predetermined time points (0.5, 2, 4, 6, 8 and 24 hr). A single dose and a multiple dose study (AGN 192024 administered b.i.d. for 9-1/2 days), were conducted. Samples were analyzed by HPLC with radiodetection. Results: AGN 192024 was a potent ocular hypotensive agent and significant reductions in intraocular pressure were achieved even with a 0.001% dose in both ocular normotensive and ocular hypertensive monkeys. The AGN 192024 distribution pattern was essentially periorbital tissues ≷ ocular surface tissues ≷ anterior segment tissues ≷ aqueous humor. Four minor metabolites were detected. Differences between AGN 192024 concentrations in the iris and ciliary body compared to the aqueous humor were striking and typically bimatoprost concentrations were 10-100 fold greater in these anterior segment tissues, notably in the multiple dose studies. Conclusion: AGN 192024 levels in the vicinity of its active site remained sufficiently elevated to account for its long-acting ocular hypotensive effects and the intact molecule appears to account for its effects on intraocular pressure. This contention is supported by the potent inherent pharmacological activity of AGN 192024.
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