The Ocular Penetration and Intraocular Pressure Lowering Effect of Topical Acetaminophen in the New Zealand White Rabbit.

IF 1.9 4区 医学 Q2 OPHTHALMOLOGY Journal of Ocular Pharmacology and Therapeutics Pub Date : 2024-10-01 Epub Date: 2024-05-27 DOI:10.1089/jop.2024.0020
Sean G Anderson, David Meyer, Eric H Decloedt
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Abstract

Purpose: Emerging data suggest that acetaminophen lowers intraocular pressure (IOP) and has the potential to be repurposed as pharmacotherapy to treat open-angle glaucoma. However, pharmacokinetic data are lacking. This study aims to describe the pharmacokinetics of topical acetaminophen and its metabolite [N-arachidonoylaminophenol (AM404)] when administered individually and in combination, and to determine its effect on IOP in the ocular normotensive adult New Zealand White Rabbit (NZWR). Methods: A randomized control trial was conducted using topical 1% acetaminophen and 1% AM404. The study was divided into two sub-studies using both paired-eye and two-eye designs. Results: The mean [95% confidence interval of the mean (95% CI)] concentration of acetaminophen detected in the aqueous humor (AH) was 4.09 ppm (3.18-5.00) at 2 h and 0.92 ppm (0.60-1.24) at 4 h after an immediate dose of topical acetaminophen. The integral IOP, defined as the integral of IOP change from baseline over time, was -5.1 mmHg⋅h (95% CI: -10 to 0.41) for control,-7.5 mmHg⋅h (95% CI: -14 to -1.1) for half-hourly acetaminophen, and -4.4 mmHg⋅h (95% CI: -14 to 5.5) for hourly acetaminophen over a 4-h period. When comparing topical acetaminophen with AM404 dosed half-hourly over a 4-h period, the integral IOP was -2.3 mmHg⋅h (95% CI: -5.9 to 1.3) for control,-2.0 mmHg⋅h (95% CI: -5.6 to 1.7) for AM404, -1.7 mmHg⋅h (95% CI: -4.5 to 1.2) for acetaminophen, and -3.2 mmHg⋅h (95% CI: -5.4 to -0.96) for acetaminophen/AM404 combined. Conclusions: Acetaminophen, but not its metabolite AM404, penetrated the multilayered cornea via passive diffusion in a dose-dependent fashion. There was a nonsignificant tendency to cause a lowering of IOP over the 4-h dosing period with higher AH concentrations of acetaminophen. Topical AM404 did not show a significant IOP-lowering effect.

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局部使用对乙酰氨基酚对新西兰白兔眼部的渗透和降低眼压效果
目的:新的数据表明,对乙酰氨基酚可降低眼压(IOP),并有可能被重新用作治疗开角型青光眼的药物疗法。然而,目前尚缺乏药代动力学数据。本研究旨在描述外用对乙酰氨基酚及其代谢物[N-arachidonoylaminophenol (AM404)]单独或联合给药时的药代动力学,并确定其对眼压正常的成年新西兰白兔(NZWR)眼压的影响。方法:采用 1%对乙酰氨基酚和 1%AM404局部用药进行随机对照试验。研究分为两项子研究,分别采用配对眼和双眼设计。研究结果在立即外用对乙酰氨基酚后 2 小时和 4 小时,在房水(AH)中检测到的对乙酰氨基酚平均浓度[平均浓度的 95% 置信区间 (95% CI)]分别为 4.09 ppm(3.18-5.00)和 0.92 ppm(0.60-1.24)。眼压积分(定义为眼压从基线随时间变化的积分):对照组为-5.1 mmHg⋅h (95% CI: -10 to 0.41),对乙酰氨基酚半小时剂量为-7.5 mmHg⋅h (95% CI: -14 to -1.1) ,对乙酰氨基酚4小时剂量为-4.4 mmHg⋅h (95% CI: -14 to 5.5)。如果将对乙酰氨基酚局部用药与在 4 小时内每半小时给药一次的 AM404 进行比较,对照组的整体眼压为-2.3 mmHg⋅h (95% CI: -5.9 to 1.3),而对照组为-2.0 mmHg⋅h (95% CI: -5.9 to 1.3)。0 mmHg⋅h (95% CI: -5.6 to 1.7),对乙酰氨基酚为-1.7 mmHg⋅h (95% CI: -4.5 to 1.2),对乙酰氨基酚/AM404联合用药为-3.2 mmHg⋅h (95% CI: -5.4 to -0.96)。结论对乙酰氨基酚(而非其代谢物 AM404)可通过被动扩散以剂量依赖的方式穿透多层角膜。对乙酰氨基酚的 AH 浓度越高,在 4 小时用药期内降低眼压的趋势就越明显。外用 AM404 未显示出明显的降低眼压效果。
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来源期刊
CiteScore
4.60
自引率
4.30%
发文量
72
审稿时长
1 months
期刊介绍: Journal of Ocular Pharmacology and Therapeutics is the only peer-reviewed journal that combines the fields of ophthalmology and pharmacology to enable optimal treatment and prevention of ocular diseases and disorders. The Journal delivers the latest discoveries in the pharmacokinetics and pharmacodynamics of therapeutics for the treatment of ophthalmic disorders. Journal of Ocular Pharmacology and Therapeutics coverage includes: Glaucoma Cataracts Retinal degeneration Ocular infection, trauma, and toxicology Ocular drug delivery and biotransformation Ocular pharmacotherapy/clinical trials Ocular inflammatory and immune disorders Gene and cell-based therapies Ocular metabolic disorders Ocular ischemia and blood flow Proliferative disorders of the eye Eyes on Drug Discovery - written by Gary D. Novack, PhD, featuring the latest updates on drug and device pipeline developments as well as policy/regulatory changes by the FDA.
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