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兽药与竞技动物:用药与兴奋剂管控问题

Veterinary medicines and competition animals: the question of medication versus doping control.

作者信息

Toutain Pierre-Louis

机构信息

UMR181 Physiopathologie et Toxicologuie Experimentales INRA, ENVT, Ecole Nationale Vétérinaire de Toulouse, 23 Chemin des Capelles 31076, Toulouse Cedex 03, France.

出版信息

Handb Exp Pharmacol. 2010(199):315-39. doi: 10.1007/978-3-642-10324-7_13.


DOI:10.1007/978-3-642-10324-7_13
PMID:20204593
Abstract

In racing and other equine sports, it is possible to increase artificially both the physical capability and the presence of a competitive instinct, using drugs, such as anabolic steroids and agents stimulating the central nervous system. The word doping describes this illegitimate use of drugs and the primary motivation of an equine anti-doping policy is to prevent the use of these substances. However, an anti-doping policy must not impede the use of legitimate veterinary medications and most regulatory bodies in the world now distinguish the control of illicit substances (doping control) from the control of therapeutic substances (medication control). For doping drugs, the objective is to detect any trace of drug exposure (parent drug or metabolites) using the most powerful analytical methods (generally chromatographic/mass spectrometric techniques). This so-called "zero tolerance rule" is not suitable for medication control, because the high level of sensitivity of current screening methods allows the detection of totally irrelevant plasma or urine concentrations of legitimate drugs for long periods after their administration. Therefore, a new approach for these legitimate compounds, based upon pharmacokinetic/pharmacodynamic (PK/PD) principles, has been developed. It involves estimating the order of magnitude of the irrelevant plasma concentration (IPC) and of the irrelevant urine concentration (IUC) in order to limit the impact of the high sensitivity of analytical techniques used for medication control. The European Horserace Scientific Liaison Committee (EHSLC), which is the European scientific committee in charge of harmonising sample testing and policies for racehorses in Europe, is responsible for estimating the IPCs and IUCs in the framework of a Risk Analysis. A Risk Analysis approach for doping/medication control involves three sequential steps, namely risk assessment, risk management, and risk communication. For medication control, the main task of EHLSC in the risk management procedure is the establishment of harmonised screening limits (HSL). The HSL is a confidential instruction to laboratories from racing authorities to screen in plasma or urine for the presence of drugs commonly used in equine medication. The HSL is derived from the IPC (for plasma) or from the IUC (for urine), established during the risk assessment step. The EHSLC decided to keep HSL confidential and to inform stakeholders of the duration of the detection time (DT) of the main medications when screening is performed with the HSL. A DT is the time at which the urinary (or plasma) concentration of a drug, in all horses involved in a trial conducted according to the EHSLC guidance rules, is shown to be lower than the HSL when controls are performed using routine screening methods. These DTs, as issued by the EHSLC (and adopted by the Fédération Equestre Internationale or FEI) provide guidance to veterinarians enabling them to determine a withdrawal time (WT) for a given horse under treatment. A WT should always be longer than a DT because the WT takes into account the impact of all sources of animal variability as well as the variability associated with the medicinal product actually administered in order to avoid a positive test. The major current scientific challenges faced in horse doping control are those instances of the administration of recombinant biological substances (EPO, GH, growth factors etc.) having putative long-lasting effects while being difficult or impossible to detect for more than a few days. Innovative bioanalytical approaches are now addressing these challenges. Using molecular tools, it is expected in the near future that transcriptional profiling analysis will be able to identify some molecular "signatures" of exposure to doping substances. The application of proteomic (i.e. the large scale investigation of protein biomarkers) and metabolomic (i.e. the study of metabolite profiling in biological samples) techniques also deserve attention for establishing possible unique fingerprints of drug abuse.

摘要

在赛马及其他马术运动中,使用合成代谢类固醇和刺激中枢神经系统的药物等兴奋剂,有可能人为提高马匹的体能和竞争本能。“兴奋剂”一词描述的就是这种非法使用药物的行为,而马术反兴奋剂政策的主要目的就是防止此类物质的使用。然而,反兴奋剂政策绝不能阻碍合法兽药的使用,目前世界上大多数监管机构都将非法物质的管控(兴奋剂检测)与治疗性物质的管控(药物管理)区分开来。对于兴奋剂药物,目标是使用最强大的分析方法(通常是色谱/质谱技术)检测任何药物暴露痕迹(母体药物或代谢物)。这种所谓的“零容忍规则”并不适用于药物管理,因为当前筛查方法的高灵敏度会在合法药物给药后的很长一段时间内检测到与实际情况完全无关的血浆或尿液浓度。因此,基于药代动力学/药效学(PK/PD)原理,针对这些合法化合物开发了一种新方法。该方法涉及估算无关血浆浓度(IPC)和无关尿液浓度(IUC)的数量级,以限制用于药物管理的分析技术高灵敏度带来的影响。欧洲赛马科学联络委员会(EHSLC)是负责协调欧洲赛马样本检测和政策的欧洲科学委员会,在风险分析框架内负责估算IPC和IUC。兴奋剂/药物管理的风险分析方法包括三个连续步骤,即风险评估、风险管理和风险沟通。对于药物管理,EHLSC在风险管理程序中的主要任务是制定统一的筛查限值(HSL)。HSL是赛马管理机构向实验室发出的机密指令,要求其在血浆或尿液中筛查马术用药中常用药物的存在情况。HSL源自风险评估步骤中确定的IPC(针对血浆)或IUC(针对尿液)。EHSLC决定对HSL保密,并在使用HSL进行筛查时告知利益相关者主要药物的检测时间(DT)。DT是指在按照EHSLC指导规则进行的试验中,所有马匹的尿液(或血浆)药物浓度在使用常规筛查方法进行检测时低于HSL的时间。EHSLC发布(并被国际马术联合会或FEI采用)的这些DT为兽医提供了指导,使他们能够确定接受治疗的特定马匹的停药时间(WT)。WT应始终长于DT,因为WT考虑了动物个体差异的所有来源以及实际给药的药品相关的变异性,以避免检测呈阳性。当前马匹兴奋剂检测面临的主要科学挑战是那些使用重组生物物质(促红细胞生成素、生长激素、生长因子等)的情况,这些物质具有假定的长期影响,且在几天以上的时间内很难或无法检测到。创新的生物分析方法正在应对这些挑战。利用分子工具,预计在不久的将来转录谱分析将能够识别出一些兴奋剂物质暴露的分子“特征”。蛋白质组学(即对蛋白质生物标志物的大规模研究)和代谢组学(即对生物样本中代谢物谱的研究)技术的应用在建立可能的药物滥用独特指纹方面也值得关注。

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Veterinary medicines and competition animals: the question of medication versus doping control.

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Why the racing industry and equestrian disciplines need to implement population pharmacokinetics: To learn, explain, summarize, harmonize, and individualize.

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[2]
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Equine Vet J. 2022-9

[3]
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[4]
Hormones as doping in sports.

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