title: The ocular effects of prostaglandins and the therapeutic potential of a new PGF2 alpha analog, PhXA41 (latanoprost), for glaucoma management.
abstract: In the early days of prostaglandin (PG) research, the infusion of large PG doses into rabbit eyes already traumatized by cannulation, led to the conclusion that PGs have a profound ocular hypertensive effect that is associated with a breakdown of the blood-aqueous barrier. In contrast, repeated topical application of PGs to nontraumatized eyes of several species other than rabbits has later been shown to yield a maintained ocular hypotensive effect, without barrier breakdown. Due to its excellent pharmacokinetic properties, the isopropyl ester form of PGF2 alpha (PGF2 alpha-IE) is a much more potent ocular hypotensive agent and appeared to be better suited for the management of glaucoma, than PGF2 alpha itself or any currently used glaucoma drug. However, even this prodrug caused clinically unacceptable foreign-body sensation and conjunctival hyperemia, which could be reduced, or eliminated, only by some modifications of the omega chain of PGF2 alpha-IE. One such analog, PhXA41, maintained highly significant IOP reduction in glaucoma patients even with once-daily application at the remarkably low concentration of 0.006%. Because PhXA41 reaches intraocular tissues and the systemic circulation in its de-esterified free-acid form, which is a good substrate for the PG transport system, it retains the most important pharmacokinetic advantages of topically applied PGF2 alpha-IE. However, its greatly reduced side effects give PhXA41 a clear therapeutic advantage over PGF2 alpha-IE, making it an effective new drug candidate for the long-term medical management of glaucoma.
authors.affiliation: Department of Ophthalmology, Columbia University, New York, NY 10032.
authors.forename: L Z
authors.initials: LZ
authors.lastname: Bito
authors.forename: J
authors.initials: J
authors.lastname: Stjernschantz
authors.forename: B
authors.initials: B
authors.lastname: Resul
authors.forename: O C
authors.initials: OC
authors.lastname: Miranda
authors.forename: S
authors.initials: S
authors.lastname: Basu
mesh_terms: D000818:Animals; D015237:Dinoprost / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D005260:Female; D005901:Glaucoma / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects / Q000502:physiology; D000077338:Latanoprost; D009883:Ophthalmic Solutions; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D011453:Prostaglandins / Q000502:physiology; D011461:Prostaglandins F, Synthetic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011817:Rabbits
chemical_list: D009883:Ophthalmic Solutions; D011355:Prodrugs; D011453:Prostaglandins; D011461:Prostaglandins F, Synthetic; C041158:prostaglandin F2 isopropyl ester; D000077338:Latanoprost; D015237:Dinoprost