The ocular effects of prostaglandins and the therapeutic potential of a new PGF2 alpha analog, PhXA41 (latanoprost), for glaucoma management.
The ocular effects of prostaglandins and the therapeutic potential of a new PGF2 alpha analog, PhXA41 (latanoprost), for glaucoma management.
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发表时间：
1993-03
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通讯作者：
L. Bito;J. Stjernschantz;B. Resul;O. C. Miranda;S. Basu
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作者：
L. Bito;J. Stjernschantz;B. Resul;O. C. Miranda;S. Basu
在前列腺素 (PG) 研究的早期阶段，将大剂量的 PG 输注到已经因插管而受伤的兔子眼睛中，得出的结论是 PG 具有严重的眼压升高作用，与血水屏障的破坏有关。相比之下，后来证明，对除兔子以外的几种物种的未受外伤的眼睛重复局部施用PG可以产生持续的降眼压作用，而不会破坏屏障。由于其优异的药代动力学特性，PGF2α 的异丙酯形式 (PGF2α-IE) 是一种更有效的降眼压剂，并且比 PGF2α 本身或任何目前使用的青光眼药物似乎更适合治疗青光眼。然而，即使是这种前药也会引起临床上不可接受的异物感和结膜充血，只有通过对 PGF2 α-IE 的 omega 链进行一些修饰才能减少或消除这种感觉。其中一种类似物 PhXA41 即使以 0.006% 的极低浓度每天使用一次，也能保持青光眼患者的 IOP 显着降低。由于 PhXA41 以去酯化游离酸形式到达眼内组织和体循环，这是 PG 转运系统的良好底物，因此它保留了局部应用的 PGF2 α-IE 最重要的药代动力学优势。然而，其大大减少的副作用使 PhXA41 比 PGF2 α-IE 具有明显的治疗优势，使其成为青光眼长期医疗管理的有效新候选药物。
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.