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.