Pharmaceutical Medical Affairs , Bausch + Lomb, Rochester, New York.
J Ocul Pharmacol Ther. 2018 Jan/Feb;34(1-2):52-60. doi: 10.1089/jop.2016.0188. Epub 2017 Aug 7.
Latanoprostene bunod (LBN) is a topical ophthalmic therapeutic for the reduction of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension (OHT). LBN is composed of latanoprost acid (LA) linked to a nitric oxide (NO)-donating moiety and is the first NO-releasing prostaglandin analog to be submitted for marketing authorization in the United States. The role of latanoprost in increasing uveoscleral outflow of aqueous humor (AqH) is well established. Herein, we review findings from nonclinical studies, which evaluated the role of NO in the IOP-lowering efficacy of LBN. Pharmacokinetic studies in rabbits and corneal homogenates indicate that LBN is rapidly metabolized to LA and butanediol mononitrate (BDMN). NO is subsequently released by BDMN as shown by increased cyclic guanosine monophosphate (cGMP) levels in (1) the AqH and iris-ciliary body after administration of LBN in rabbits and in (2) human trabecular meshwork (TM) cells after incubation with LBN. LBN reduced myosin light chain phosphorylation, induced cytoskeletal rearrangement, and decreased resistance to current flow to a greater extent than latanoprost in TM cells, indicating that NO released from LBN elicited TM cell relaxation. LBN also lowered IOP to a greater extent than latanoprost in FP receptor knockout mice, rabbits with transient OHT, glaucomatous dogs, and primates with OHT. Along with results from a Phase 2 clinical study in which treatment with LBN 0.024% resulted in greater IOP-lowering efficacy than latanoprost 0.005%, these data indicate that LBN has a dual mechanism of action, increasing AqH outflow through both the uveoscleral (using LA) and TM/Schlemm's canal (using NO) pathways.
拉坦前列素丁基（LBN）是一种局部眼科治疗药物，用于降低开角型青光眼或高眼压（OHT）患者的眼内压（IOP）。LBN 由拉坦前列酸（LA）与一氧化氮（NO）供体部分连接而成，是第一个在美国提交营销授权申请的释放 NO 的前列腺素类似物。拉坦前列素在增加房水（AqH）的葡萄膜巩膜流出方面的作用已得到充分证实。在此，我们回顾了非临床研究的结果，这些研究评估了 NO 在 LBN 降低 IOP 疗效中的作用。在兔子和角膜匀浆中的药代动力学研究表明，LBN 迅速代谢为 LA 和丁二醇单硝酸酯（BDMN）。BDMN 随后释放 NO，这表现在（1）兔子给予 LBN 后 AqH 和虹膜睫状体以及（2）用 LBN 孵育后人类小梁网（TM）细胞中环鸟苷单磷酸（cGMP）水平增加。LBN 降低了肌球蛋白轻链磷酸化，诱导细胞骨架重排，并比 TM 细胞中的拉坦前列素更能降低对电流的阻力，表明 LBN 释放的 NO 引起 TM 细胞松弛。LBN 在 FP 受体敲除小鼠、一过性 OHT 兔子、青光眼犬和 OHT 灵长类动物中的 IOP 降低程度也大于拉坦前列素。与 LBN 0.024%治疗在 FP 受体敲除小鼠中导致比拉坦前列素 0.005%治疗更大程度降低 IOP 的 2 期临床研究结果一起，这些数据表明 LBN 具有双重作用机制，通过葡萄膜巩膜（使用 LA）和 TM/施莱姆氏管（使用 NO）途径增加房水流出。
