Nicox Research Institute, Milan, Italy.
University of Nebraska Medical Center, Omaha, Nebraska, USA.
J Ocul Pharmacol Ther. 2021 May;37(4):215-222. doi: 10.1089/jop.2020.0126. Epub 2021 Feb 15.
We studied the IOP-lowering effects of NCX 1741, a novel nitric oxide (NO)-donating derivative of the phosphodiesterase type-5 inhibitor, avanafil, in Cynomolgus monkey with laser-induced ocular hypertension (OHT-monkeys). NCX 1193 (NO-donating moiety), NCX 1744 (NCX 1741 without ester nitrate moiety), and travoprost (PGF2α analogue) were used for comparison. Ocular exposure after NCX 1741 dosing also was addressed. Vehicle (phosphate buffer pH 6.0, Kolliphor 5%, DMSO 0.3%, benzalkonium chloride 0.02%), NCX 1741, NCX 1193, NCX 1744, or travoprost were instilled (30 μL; single dose) masked and conscious IOPs were measured by pneumatonometry. LC-MS/MS-based methods were employed to monitor ocular exposure of NCX 1741 and main metabolites after ocular dosing in New Zealand White rabbits. NCX 1741 (2.2%, 0.8 μmol/eye) lowered IOP with an E (ΔΔIOP, IOP change vs. pre-dose and vehicle) between 5 and 8 h post-dosing (ΔΔIOP, -5.3 ± 2.0 mmHg and ΔΔIOP, -6.0 ± 2.1 mmHg). Conversely, equimolar (0.47%, 0.8 μmol/eye) NCX 1193 IOP-lowering effects were maximal 3 h post-dosing (ΔΔIOP, -4.7 ± 1.6 mmHg) and declined thereafter (ΔΔIOP, -1.6 ± 1.1 mmHg). In a follow-up study, NCX 1741 (1.5%, 0.5 μmol/eye) was more effective than NCX 1744 despite a similar duration. Further, NCX 1741 was as effective as travoprost (0.1%, 0.06 μmol/eye) at 5 and 8 h post-dosing (travoprost, ΔΔIOP, -3.4 ± 2.2 mmHg and ΔΔIOP, -4.9 ± 1.3 mmHg) but had shorter duration (NCX 1741, ΔΔIOP, -1.5 ± 1.1 mmHg; travoprost, ΔΔIOP, -7.1 ± 2.8 mmHg). NCX 1741 resulted in significant aqueous humor exposure, as determined by the levels of the main metabolite, avanafil. NCX 1741 rapidly and effectively lowers IOP in OHT-monkeys for several hours post-dosing. How these effects translate in humans is still to be defined.
我们研究了新型一氧化氮（NO）供体磷酸二酯酶 5 抑制剂阿伐那非衍生物 NCX 1741 在激光诱导的猴眼高压（OHT 猴）中的降眼压作用。NCX 1193（NO 供体部分）、NCX 1744（不含酯硝酸盐部分的 NCX 1741）和曲伏前列素（PGF2α 类似物）用于比较。还研究了 NCX 1741 给药后的眼部暴露情况。将载体（磷酸缓冲液 pH6.0、Kolliphor5%、DMSO0.3%、苯扎氯铵 0.02%）、NCX 1741、NCX 1193、NCX 1744 或曲伏前列素（30μL；单次剂量）注入蒙眼清醒的 IOP 由气动眼压计测量。采用基于 LC-MS/MS 的方法监测新西兰白兔眼部给药后 NCX 1741 及其主要代谢物的眼部暴露情况。NCX 1741（2.2%，0.8μmol/眼）在给药后 5 至 8 小时降低 IOP（ΔΔIOP，与给药前和载体相比的 IOP 变化）（ΔΔIOP，-5.3±2.0mmHg 和 ΔΔIOP，-6.0±2.1mmHg）。相反，等摩尔（0.47%，0.8μmol/眼）NCX 1193 的降眼压作用在给药后 3 小时达到最大（ΔΔIOP，-4.7±1.6mmHg），此后下降（ΔΔIOP，-1.6±1.1mmHg）。在后续研究中，尽管持续时间相似，但 NCX 1741（1.5%，0.5μmol/眼）比 NCX 1744 更有效。此外，NCX 1741 在给药后 5 小时和 8 小时与曲伏前列素（0.1%，0.06μmol/眼）同样有效（曲伏前列素，ΔΔIOP，-3.4±2.2mmHg 和 ΔΔIOP，-4.9±1.3mmHg），但持续时间更短（NCX 1741，ΔΔIOP，-1.5±1.1mmHg；曲伏前列素，ΔΔIOP，-7.1±2.8mmHg）。NCX 1741 导致主要代谢物阿伐那非的水平显著增加，表明房水暴露。NCX 1741 在 OHT 猴中快速有效地降低眼压，持续数小时。这些作用在人类中的转化仍有待确定。
