Ethington Jason, Goldmeier David, Gaynes Bruce I
Department of Ophthalmology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL.
Cornea. 2017 Mar;36(3):363-366. doi: 10.1097/ICO.0000000000001125.
To identify pharmacodynamic (PD) and pharmacokinetic (PK) metrics that aid in mechanistic understanding of dosage considerations for prolonged corneal anesthesia.
A rabbit model using 0.5% tetracaine hydrochloride was used to induce corneal anesthesia in conjunction with Cochet-Bonnet anesthesiometry. Metrics were derived describing PD-PK parameters of the time-dependent domain of recovery in corneal sensitivity. Curve fitting used a 1-phase exponential dissociation paradigm assuming a 1-compartment PK model. Derivation of metrics including half-life and mean ligand residence time, tau (τ), was predicted by nonlinear regression. Bioavailability was determined by area under the curve of the dose-response relationship with varying drop volumes.
Maximal corneal anesthesia maintained a plateau with a recovery inflection at the approximate time of predicted corneal drug half-life. PDs of recovery of corneal anesthesia were consistent with a first-order drug elimination rate. The mean ligand residence time (tau, τ) was 41.7 minutes, and half-life was 28.89 minutes. The mean estimated corneal elimination rate constant (ke) was 0.02402 minute. Duration of corneal anesthesia ranged from 55 to 58 minutes. There was no difference in time domain PD area under the curve between drop volumes.
Use of a small drop volume of a topical anesthetic (as low as 11 μL) is bioequivalent to conventional drop size and seems to optimize dosing regiments with a little effect on ke. Prolongation of corneal anesthesia may therefore be best achieved with administration of small drop volumes at time intervals corresponding to the half-life of drug decay from the corneal compartment.
确定有助于从机制上理解延长角膜麻醉剂量考量的药效学（PD）和药代动力学（PK）指标。
采用0.5%盐酸丁卡因的兔模型结合科谢 - 博内眼压计诱导角膜麻醉。得出描述角膜敏感性恢复时间依赖性域的PD - PK参数的指标。曲线拟合采用假设为单室PK模型的1相指数解离范式。通过非线性回归预测包括半衰期和平均配体驻留时间τ等指标的推导。通过不同滴量的剂量 - 反应关系曲线下面积确定生物利用度。
最大角膜麻醉维持在一个平台期，在预测的角膜药物半衰期左右出现恢复拐点。角膜麻醉恢复的PD与一级药物消除率一致。平均配体驻留时间（τ）为41.7分钟，半衰期为28.89分钟。平均估计角膜消除速率常数（ke）为0.02402分钟。角膜麻醉持续时间为55至58分钟。不同滴量之间曲线下面积的时域PD无差异。
使用小滴量的局部麻醉剂（低至11μL）与传统滴量具有生物等效性，并且似乎能优化给药方案，对ke影响较小。因此，通过以与角膜隔室药物衰减半衰期相对应的时间间隔给予小滴量药物，可能最能实现角膜麻醉的延长。
