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抗蛇毒血清药代动力学和药效学的全球参数优化和敏感性分析。

Global parameter optimisation and sensitivity analysis of antivenom pharmacokinetics and pharmacodynamics.

机构信息

Department of Engineering Mathematics, Ada Lovelace Building, University of Bristol, University Walk, Bristol, BS8 1TW, UK.

出版信息

Toxicon. 2023 Aug 15;232:107206. doi: 10.1016/j.toxicon.2023.107206. Epub 2023 Jun 23.

Abstract

In recent years it has become possible to design snakebite antivenoms with diverse pharmacokinetic properties. Owing to the pharmacokinetic variability of venoms, the choice of antivenom scaffold may influence a treatment's neutralisation coverage. Computation offers a useful medium through which to assess the pharmacokinetics and pharmacodynamics of envenomation-treatment systems, as antivenoms with identical neutralising capacities can be simulated. In this study, we simulate envenomation and treatment with a variety of antivenoms, to define the properties of effective antivenoms. Systemic envenomation and treatment were described using a two-compartment pharmacokinetic model. Treatment of Naja sumatrana and Cryptelytrops purpureomaculatus envenomation was simulated with a set of 200,000 theoretical antivenoms across 10 treatment time delays. These two venoms are well-characterised and have differing pharmacokinetic properties. The theoretical antivenom set varied across molecular weight, dose, k, k, and valency. The best and worst treatments were identified using an area under the curve metric, and a global sensitivity analysis was performed to quantify the influence of the input parameters on treatment outcome. The simulations show that scaffolds of diverse molecular formats can be effective. Molecular weight and valency have a negligible direct impact on treatment outcome, however low molecular weight scaffolds offer more flexibility across the other design parameters, particularly when treatment is delayed. The simulations show k to primarily mediate treatment efficacy, with rates above 10 Ms required for the most effective treatments. k has the greatest impact on the performance of less effective scaffolds. While the same scaffold preferences for improved treatment are seen for both model snakes, the parameter bounds for C. purpureomaculatus envenomation are more constrained. This paper establishes a computational framework for the optimisation of antivenom design.

摘要

近年来,设计具有不同药代动力学特性的蛇伤抗毒血清已成为可能。由于毒液的药代动力学变异性,抗毒血清支架的选择可能会影响治疗的中和覆盖范围。计算为评估中毒-治疗系统的药代动力学和药效动力学提供了一个有用的媒介,因为可以模拟具有相同中和能力的抗毒血清。在这项研究中,我们模拟了各种抗毒血清的中毒和治疗,以确定有效抗毒血清的特性。使用两室药代动力学模型描述全身中毒和治疗。用一组 20 万种理论抗毒血清模拟 Naja sumatrana 和 Cryptelytrops purpureomaculatus 中毒和治疗,治疗时间延迟 10 次。这两种毒液具有良好的特征,并且具有不同的药代动力学特性。理论抗毒血清集在分子量、剂量、k、k 和价态方面有所不同。使用曲线下面积度量来确定最佳和最差的治疗方法,并进行全局敏感性分析以量化输入参数对治疗结果的影响。模拟表明,不同分子结构的支架都可以有效。分子量和价态对治疗结果的直接影响可以忽略不计,但是低分子量支架在其他设计参数方面提供了更大的灵活性,尤其是在治疗延迟的情况下。模拟表明 k 主要介导治疗效果,最有效的治疗需要超过 10 Ms 的速率。k 对效果较差的支架的性能影响最大。虽然对于两种模型蛇,都可以看到改善治疗的相同支架偏好,但 C. purpureomaculatus 中毒的参数范围更受限制。本文建立了抗毒血清设计优化的计算框架。

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