GLAUCOMA--NEW DRUGS AND MECHANISMS OF AQUEOUS SECRETION

拟议的工作分为四个相关类别，全部汇聚 关于房水形成和青光眼治疗的问题： 新药开发（外用碳酸酐酶抑制剂）；研究 房水分泌的离子反应；效果探索 A1C13 和其他酸对房水分泌和睫状突 pH 值的影响； 自主神经药物和Na-K-ATP酶抑制剂对电解质的影响 从血浆到水的运动。 1.) 我们正在寻找一种外用碳酸酐酶抑制剂 特性使得 1 滴溶液可降低眼内压 男人6-12小时。 这需要在有机合成方面不断努力， 化合物和房水的理化性质分析 动物和人类的动态。 这个目标的可行性似乎是合理的；它 已经在兔子身上实现了。 几乎可以肯定，这样的化合物 对人体不会产生全身毒性，也不会对眼睛产生任何其他影响。 2.）我们相信有可能（可能？）在房水中（和其他 分泌位点，如脑脊液和胰腺），观察到的联系 Na 和 HCO3- 的离子配对具有特定的化学基础，NaCO3- 和 NaHCO3 度。 这尚未考虑到上皮分泌 但已被认为是红细胞中 HCO3- - Cl- 交换的基础。 在这种观点中，Na 不是流体形成的推动力，但 Na 是 掺入阴离子或未解离的分子中。 我们将调查 这个；如果属实，这个新概念应该会深刻影响离子的研究 运输。 3.) 我们继续研究刘易斯或布朗斯特德的质子化发现 酸减少或消除房水分泌。 这有理论上的 对分泌机制的影响并提供了可能性 通过新方法减少房水分泌。 在此背景下，我们将 还研究了纤毛过程的 pH 值以及酸如何改变它 或通过碳酸酐酶抑制剂。 4.) 我们将测量离子从等离子体移动到水相的速率 幽默，在服用已知的各类药物之前和之后 影响水液分泌，就像我们对碳酸酐酶所做的那样 抑制剂。 这是眼药理学中被忽视的一个方面。我们将 研究哇巴因、噻吗洛尔、毛果芸香碱、肾上腺素和其他几种药物。 这样的 测量应该揭示它们的（目前未知的）机制。

The proposed work is divided into four related categories, all converging on the problems of aqueous humor formation and treatment of glaucoma: Development of new drugs (topical carbonic anhydrase inhibitors); study of ionic reactions underlying secretion of aqueous; exploration of the effect of A1C13 and other acids on aqueous secretion and pH of ciliary processes; effect of autonomic drugs and Na-K-ATPase inhibitors on electrolyte movement from plasma to aqueous. 1.) We are searching for a topical carbonic anhydrase inhibitor with properties such that 1 drop of solution will lower intraocular pressure in man for 6-12 hours. This demands a continuing effort in organic synthesis, analysis of physico-chemical properties of compounds, and aqueous humor dynamics in animals and man. Feasibility of this goal seems reasonable; it has already been achieved in the rabbit. Almost certainly, such a compound will have no systemic toxicity in man, or any other effect on the eye. 2.) We believe it possible (likely?) that in aqueous humor (and other secretory sites, as cerebrospinal fluid and pancreas), the observed linkage of Na+ and HCO3- has a specific chemical basis, in ion pairing of NaCO3- and NaHCO3-degrees. This has not been considered for epithelial secretion but has been entertained as a basis for HCO3- - Cl- exchange in red cells. In this view Na+ is not the moving force for fluid formation, but Na is incorporated into an anion or undissociated molecule. We shall investigate this; if true, the new concept should profoundly affect studies of ion transport. 3.) We continue to study our finding that protonation by Lewis or Bronsted acids reduces or abolishes aqueous humor secretion. This has theoretical implications for mechanisms of secretion and offers the possibility of reduction of aqueous secretion by new methods. In this context we shall also study the pH of ciliary process and how this may be changed by acids or by carbonic anhydrase inhibitors. 4.) We shall measure the rates of ion movement from plasma to aqueous humor, before and after administration of various classes of drugs known to affect aqueous secretion, as we have done with carbonic anhydrase inhibitors. This is a neglected aspect of ocular pharmacology; we shall study ouabain, timolol, pilocarpine, epinephrine, and several others. Such measurements should throw light on their (presently unknown) mechanism.