Bito L Z
Ophthalmology Research, Columbia University, New York, NY 10032.
Prog Clin Biol Res. 1989;312:329-47.
It appears that a pragmatic approach, based entirely on the ability of a drug or procedure to reduce IOP, has thus far been used to develop modalities for the management of glaucoma. Barring serendipity, it is unlikely that this approach will produce effective new methods for the management of this ocular disorder, which presents an ever-increasing problem in an increasingly longevous and industrialized world population. Although a better understanding of the biology of aqueous humor dynamics and its pathogenesis, combined with new genetic engineering techniques, may eventually lead to the total elimination of glaucoma, that ultimate solution is unlikely to be achieved within the foreseeable future. Thus, a physiologic approach to glaucoma management must be developed, one that takes into consideration all of our recently acquired knowledge of aqueous humor dynamics and all other relevant physiologic principles. A review of currently available information suggests that from a physiologic point of view the best approach to glaucoma management, at least for the next few decades, will be based on the use of receptor-mediated, naturally occurring ocular hypotensive agents, or at least agents that closely resemble such naturally occurring autacoids. Based on the temporal and spatial limitations of the various classes of receptor-mediated autacoids and on differences in the specificity and the nature of the responses they elicit at different sites, we conclude that a physiologic approach to glaucoma management should focus on the use of topically applied local hormones or their analogs. This approach appears to be feasible in light of demonstrations that several members of one family of local hormones, the eicosanoids that are produced within ocular tissues under physiological conditions are effective ocular hypotensive agents. It has been shown that one member of this family, PGF2 alpha, in its esterified form, is an extremely potent ocular hypotensive agent in its esterified prodrug form in both normotensive and glaucomatous human eyes, yielding significant IOP reduction when topically applied in doses less than one-hundredth that of currently available glaucoma medications. Although no intraocular side effects have been noted in human eyes after topical application of PGF2 alpha-1-isopropylester in submaximal ocular hypotensive doses, such side effects as conjunctival hyperemia and foreign body sensation present a problem and a challenge.4
到目前为止，青光眼治疗方法的开发似乎完全基于药物或手术降低眼压的能力，采取了一种实用主义的方法。除非机缘巧合，否则这种方法不太可能产生治疗这种眼部疾病的有效新方法，而在日益长寿和工业化的世界人口中，青光眼问题正日益严重。尽管对房水动力学及其发病机制的生物学有了更好的理解，再加上新的基因工程技术，最终可能会彻底消除青光眼，但在可预见的未来不太可能实现这一最终解决方案。因此，必须开发一种青光眼治疗的生理学方法，这种方法要考虑到我们最近获得的关于房水动力学的所有知识以及所有其他相关的生理学原理。对现有信息的回顾表明，从生理学角度来看，至少在未来几十年里，青光眼治疗的最佳方法将基于使用受体介导的天然存在的降眼压药物，或者至少是与这种天然存在的自分泌调节物质非常相似的药物。基于各类受体介导的自分泌调节物质的时间和空间局限性，以及它们在不同部位引发的反应的特异性和性质差异，我们得出结论，青光眼治疗的生理学方法应侧重于局部应用局部激素或其类似物。鉴于有证据表明，一类局部激素（即生理条件下在眼组织内产生的类二十烷酸）中的几个成员是有效的降眼压药物，这种方法似乎是可行的。已经表明，该家族的一个成员，PGF2α，以其酯化形式，在正常血压和青光眼患者眼中，其酯化前药形式都是一种极其有效的降眼压药物，局部应用剂量小于目前可用青光眼药物剂量的百分之一时，眼压会显著降低。尽管局部应用低于最大降眼压剂量的PGF2α - 1 - 异丙酯后，人眼中未观察到眼内副作用，但结膜充血和异物感等副作用仍是一个问题和挑战。
