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首页> 外文学位 >Pharmacometrie de la ropivacaine suivant l'anesthesie locoregionale chez les patients orthopediques : Caracterisation de l'intensite et de la duree du bloc sensitif.
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Pharmacometrie de la ropivacaine suivant l'anesthesie locoregionale chez les patients orthopediques : Caracterisation de l'intensite et de la duree du bloc sensitif.

机译：骨科患者局部麻醉后罗哌卡因的药理作用：感觉障碍的强度和持续时间的特征。

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摘要

Background and Objectives: To provide postoperative analgesia, the anesthesiologist has at his disposal a panel of different medications and also regional techniques of neural blockade. Loco-regional analgesia (central or peripheral) blocks conduction of painful influx to the central nervous system by the use of local anesthetics (LA). Among these drugs, ropivacaine (ROP), has an enormous potential given is long-acting efficacy and low incidence of toxicity. Currently, ROP is not licensed for use in spinal anesthesia (central block) in all countries due to a lack of data from controlled clinical trials. So far, research efforts on this topic have mainly focused on safety and dose-finding issues. In addition, the most appropriate dose for a peripheral nerve block has never been estimated empirically. Dosing recommendation for LAs should be site-specific and adapted to the intensity of the stimuli produced by a surgery and to the duration of analgesia required. Ultimately, these should guide clinicians in identifying the most appropriate block for the individual patients by taking into account demographic factors that may affect the pharmacokinetics (PK) and pharmacodynamics (PD) of LA overall objective of the current research).;Analytical Method Validation Manuscript 1: First, a specific and sensitive assay has been developed and validated for the determination of ROP in human plasma.;Biomarker Validation Manuscript 2: Second, the reliability of a neurostimulator measuring current perception threshold (CPT) was assessed in healthy volunteers. The device uses a constant transcutaneous electrical sine wave stimulus at different frequencies specific to pain-conducting fibers. Our results suggest that CPT are reliable and can be applied to characterize, in a quantitative manner, the sensory onset of a peripheral nerve block in a clinical setting.;Clinical Studies Manuscript 3: The systemic absorption of ROP after a femoral nerve block in orthopedic patients was then characterized using extended rich PK-sampling, i.e. up to 4 days post-dosing. Our model used for data analysis confirms that, in a similar manner to neuraxial sites of LAs injection, the systemic absorption of ROP from the femoral space is biphasic, i.e. a rapid initial phase (mean absorption time of 25 min, % CI: 19 -- 38 min) followed by a much slower phase (half-life (T1/2) of 3.9 h, % CI: 2.9 -- 6.0 h). A significant age-related increase in the permeability of the LA was also observed in our elderly patients (n = 19, age = 62.6 +/- 7.1 yr).;Manuscript 4: A population PK-PD analysis of the sensory anesthesia (CPT) of ROP using our PK model was also performed. The effect-site amount producing 90% of the maximum possible effect (AE90) was estimated as 20.2 +/- 10.1 mg. At 2 x AE90, the sigmoid E max model predicted an onset time of 23.4 +/- 12.5 min and a duration of 22.9 +/- 5.3 h. To the best of our knowledge, this is the first PK-PD model developed for a peripheral nerve block.;Manuscript 5: In the third and last study, a similar approach was used to characterise the PK-PD relationship of intrathecally administered ROP in patients undergoing minor lower limb surgery. The biphasic release of the agent from the intrathecal space was modeled using a rapid initial absorption phase (T1/2 of 49 min, % CI: 24 -- 77 min) followed (lag-time of ∼ 18 +/- 2 min) by a slightly slower input rate (T1/2 of 66 min, % CI: 36 -- 97 min). ROP maximal response was observed within 12.6 +/- 4.9 min of dosing, with a subsequent return to baseline 210 +/- 55 min after the administration of the LA. The effect-site amount producing 50 % of the Emax (AE50) was estimated at 7.3 +/- 2.3 mg.;Conclusion: Altogether, the proposed models can be used to predict the time-course of sensory blockade after a femoral nerve block and spinal anesthesia using ROP and to optimize dosing regimen according to clinical needs with regard to important cofactors such as age.
机译：背景与目的：为了提供术后镇痛作用，麻醉师可以使用一组不同的药物以及区域性神经阻滞技术。局部区域镇痛（中央或周围镇痛）通过使用局部麻醉药（LA）阻止疼痛性涌入传导至中枢神经系统。在这些药物中，罗哌卡因（ROP）具有长效疗效和低毒性发生的巨大潜力。目前，由于缺乏对照临床试验的数据，ROP尚未在所有国家/地区获得许可用于脊髓麻醉（中央阻滞）。到目前为止，有关该主题的研究工作主要集中在安全性和剂量寻找问题上。此外，从未凭经验估算出末梢神经阻滞的最合适剂量。 LAs的剂量建议应针对特定地点，并适合手术产生的刺激强度和所需的镇痛持续时间。最终，这些方法应指导临床医生考虑到可能影响当前研究总体目标的LA药代动力学（PK）和药代动力学（PD）的人口统计学因素，从而为个体患者确定最合适的阻滞剂。；《分析方法验证手稿》 1：首先，已开发出一种特异性和灵敏的测定方法，并已用于测定人血浆中ROP的有效性。；生物标志物验证手稿2：其次，在健康志愿者中评估了测量电流感知阈值（CPT）的神经刺激器的可靠性。该设备在特定于疼痛传导纤维的不同频率上使用恒定的经皮电正弦波刺激。我们的结果表明CPT是可靠的，并且可以在临床中用于定量表征周围神经阻滞的感觉发作。;临床研究手稿3：在骨科中股骨神经阻滞后ROP的全身吸收然后使用扩展的丰富PK采样（即给药后最多4天）对患者进行特征化。我们用于数据分析的模型证实，以与LAs注射的神经轴位类似的方式，股骨腔内ROP的系统吸收是双相的，即一个快速的初始阶段（平均吸收时间为25分钟，％CI：19- -38分钟），然后是慢得多的阶段（半衰期（T1 / 2）为3.9小时，％CI：2.9-6.0小时）。在我们的老年患者中（n = 19，年龄= 62.6 +/- 7.1岁），还观察到了LA的通透性与年龄相关的显着增加。；手稿4：感觉麻醉的人群PK-PD分析（CPT）还使用我们的PK模型执行了ROP）。产生最大可能效应（AE90）的90％的效应位点量估计为20.2 +/- 10.1 mg。在2 x AE90时，乙状结肠E max模型预测发作时间为23.4 +/- 12.5分钟，持续时间为22.9 +/- 5.3小时。据我们所知，这是针对周围神经阻滞开发的第一个PK-PD模型。；稿件5：在第三项也是最后一项研究中，采用了类似的方法来表征鞘内施用ROP的PK-PD关系。下肢小手术的患者。使用快速初始吸收阶段（T1 / 2为49分钟，％CI：24-77分钟），然后（约18 +/- 2分钟的滞后时间）对药物从鞘内空间的双相释放进行建模输入速度稍慢（T1 / 2为66分钟，％CI：36-97分钟）。在给药后的12.6 +/- 4.9分钟内观察到ROP最大反应，随后在服用LA后210 +/- 55分钟恢复到基线。估计产生Emax（AE50）的50％的作用部位数量为7.3 +/- 2.3 mg。结论：总的来说，所提出的模型可用于预测股神经阻滞和神经阻滞后感觉障碍的时程。使用ROP进行脊髓麻醉，并根据临床需求针对重要的辅助因子（例如年龄）优化给药方案。

著录项

  • 作者

    Gaudreault, Francois.;

  • 作者单位

    Universite de Montreal (Canada).;

  • 授予单位 Universite de Montreal (Canada).;
  • 学科 Health Sciences Pharmacology.;Health Sciences Pharmacy.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 223 p.
  • 总页数 223
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 肿瘤学;
  • 关键词

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