Translational Pre-Clinical Model Platform, Singapore Institute of Eye Research (SERI).
ACP in Ophthalmology & Visual Sciences, DUKE-NUS Graduate Medical School, Singapore.
Am J Physiol Cell Physiol. 2024 May 1;326(5):C1505-C1519. doi: 10.1152/ajpcell.00617.2023. Epub 2024 Apr 1.
Glaucoma is a blinding disease. Reduction of intraocular pressure (IOP) is the mainstay of treatment, but current drugs show side effects or become progressively ineffective, highlighting the need for novel compounds. We have synthesized a family of perhydro-1,4-oxazepine derivatives of digoxin, the selective inhibitor of Na,K-ATPase. The cyclobutyl derivative (DcB) displays strong selectivity for the human α2 isoform and potently reduces IOP in rabbits. These observations appeared consistent with a hypothesis that in ciliary epithelium DcB inhibits the α2 isoform of Na,K-ATPase, which is expressed strongly in nonpigmented cells, reducing aqueous humor (AH) inflow. This paper extends assessment of efficacy and mechanism of action of DcB using an ocular hypertensive nonhuman primate model (OHT-NHP) (). In OHT-NHP, DcB potently lowers IOP, in both acute (24 h) and extended (7-10 days) settings, accompanied by increased aqueous humor flow rate (AFR). By contrast, ocular normotensive animals (ONT-NHP) are poorly responsive to DcB, if at all. The mechanism of action of DcB has been analyzed using isolated porcine ciliary epithelium and perfused enucleated eyes to study AH inflow and AH outflow facility, respectively. ) DcB significantly stimulates AH inflow although prior addition of 8-Br-cAMP, which raises AH inflow, precludes additional effects of DcB. ) DcB significantly increases AH outflow facility via the trabecular meshwork (TM). Taken together, the data indicate that the original hypothesis on the mechanism of action must be revised. In the OHT-NHP, and presumably other species, DcB lowers IOP by increasing AH outflow facility rather than by decreasing AH inflow. When applied topically, a cyclobutyl derivative of digoxin (DcB) potently reduces intraocular pressure in an ocular hypertensive nonhuman primate model (), associated with increased aqueous humor (AH) flow rate (AFR). The mechanism of action of DcB involves increased AH outflow facility as detected in enucleated perfused porcine eyes and, in parallel, increased (AH) inflow as detected in isolated porcine ciliary epithelium. DcB might have potential as a drug for the treatment of open-angle human glaucoma.
青光眼是一种致盲性疾病。降低眼内压（IOP）是治疗的主要手段，但目前的药物显示出副作用或逐渐失效，这凸显了对新型化合物的需求。我们合成了一组地高辛的全氢-1,4-噁嗪衍生物，地高辛是 Na,K-ATP 酶的选择性抑制剂。环丁基衍生物（DcB）对人α2 同工型具有很强的选择性，并能有效降低兔眼内压。这些观察结果似乎与一个假设一致，即在睫状上皮中，DcB 抑制强烈表达于非色素细胞的 Na,K-ATP 酶的α2 同工型，从而减少房水（AH）的流入。本文通过使用眼高压非人灵长类动物模型（OHT-NHP）（）进一步评估了 DcB 的疗效和作用机制。在 OHT-NHP 中，DcB 可在急性（24 小时）和延长（7-10 天）设置中强力降低 IOP，同时增加房水流量（AFR）。相比之下，眼正常压动物（ONT-NHP）对 DcB 的反应很差，如果有的话。通过使用分离的猪睫状上皮和灌注去眼来分别研究房水的流入和房水流出能力，分析了 DcB 的作用机制。）DcB 显著刺激房水的流入，尽管预先加入 8-Br-cAMP 会增加房水的流入，但会排除 DcB 的其他作用。）DcB 通过小梁网（TM）显著增加房水流出能力。综上所述，数据表明，关于作用机制的原始假设必须修改。在 OHT-NHP 中，推测在其他物种中，DcB 通过增加房水流出能力而不是减少房水流入来降低眼内压。局部应用地高辛的环丁基衍生物（DcB）可强力降低眼高压非人灵长类动物模型（）的眼内压，同时伴随着房水（AH）流量（AFR）的增加。DcB 的作用机制涉及到在去眼灌注的猪眼中检测到的房水流出能力的增加，以及在分离的猪睫状上皮中检测到的房水（AH）流入的增加。DcB 可能具有作为治疗开角型人类青光眼的药物的潜力。
