title: Ocular hypotensive and aqueous outflow-enhancing effects of AL-3037A (sodium ferri ethylenediaminetetraacetate).
abstract: AL-3037A (Sodium ferri ethylenediaminetetraacetate), a novel compound shown to stimulate the degradation of glycosaminoglycans, was evaluated for its effects on aqueous humor outflow and intraocular pressure (IOP) in four experimental models. Its effect on outflow facility was assessed in bovine and human ocular perfusion organ cultures. Its IOP effect was tested in normotensive and dexamethasone-induced ocular hypertensive rabbits. In bovine eyes, perfusion with AL-3037A (0.1% w/v, 2.3 m M) significantly increased the outflow facility well above the normal 'wash-out' effect. At 30 min after perfusion, the outflow facility of drug-treated eyes increased by 26.0+/-2.8% (mean +/- S.E.(M.), n = 8), significantly higher than the 12.1 +/- 2.8% increase in vehicle-treated eyes. This difference sustained throughout the study period (2 hr). The compound also enhanced aqueous outflow in perfused human anterior segments. In non-glaucomatous eyes, it produced a small decrease in IOP (15.4 +/- 4.6%, n = 17), but in tissues derived from glaucoma patients, bolus administration of 3 mg (7 micromol) of AL-3037A lowered the IOP by 52-68% (n = 2) lasting for at least 3 hr. This outflow-enhancing effect of AL-3037A in ex vivo studies was confirmed by in vivo results. In normotensive rabbits, oral (50 mg kg(-1)), intravenous (10 mg kg(-1)), or topical (2 mg; 50 microl of 4% w/v solution) administration of AL-3037A produced maximum reduction of IOP, when compared to vehicle-treated animals, by 34.7+/-3.5% (n = 10), 22.0 +/- 4.6% (n = 10), and 21.6 +/-4.5% (n = 10), respectively. In dexamethasone induced ocular hypertensive rabbits, topical application of the compound (0.5 mg; 25 microl of 2% w/v solution) reduced IOP significantly by 19.2+/- 0.4% (n = 7) at 3 hr after dosing. Importantly, the IOP lowering effect of AL-3037A did not diminish even after repeated treatments in consecutive days. Thus, in the four study models across three animal species, AL-3037A was demonstrated to be an efficacious ocular hypotensive compound whose effect is most likely mediated by augmentation of the aqueous outflow. Its proposed action on the metabolism of glycosaminoglycans may provide a new and unique mechanism for the treatment of glaucoma.
authors.affiliation: Alcon Research, Ltd, 6201 South Freeway, Fort Worth, TX 76134, USA.
authors.forename: I H
authors.initials: IH
authors.lastname: Pang
authors.forename: H
authors.initials: H
authors.lastname: Moll
authors.forename: M A
authors.initials: MA
authors.lastname: McLaughlin
authors.forename: P A
authors.initials: PA
authors.lastname: Knepper
authors.forename: L
authors.initials: L
authors.lastname: De Santis
authors.forename: D L
authors.initials: DL
authors.lastname: Epstein
authors.forename: A F
authors.initials: AF
authors.lastname: Clark
mesh_terms: D000818:Animals; D001082:Aqueous Humor / Q000187:drug effects*; D002417:Cattle; D005290:Ferric Compounds / Q000494:pharmacology; D005901:Glaucoma / Q000188:drug therapy; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects*; D008854:Microscopy, Electron / Q000379:methods; D009798:Ocular Hypertension / Q000188:drug therapy; D009924:Organ Culture Techniques; D011817:Rabbits
chemical_list: C448439:AL3037A; D005290:Ferric Compounds