系列介绍：View all articles in this series.
管理的agencies require that any drug (parent or major metabolite) that penetrates the brain and has CNS activity, regardless of its therapeutic indication, be assessed for that drug’s abuse potential. In this评估滥用可能性系列, we are sharing how we design and setup accurate and valid nonclinical GLP abuse liability study types required by regulatory agencies: self-administration, drug discrimination and physical dependency.
Below is a short summary of the full-length article (available for download) that explores how to design a drug discrimination study with in-house data samples from Covance.
关于药物鉴别测试
药物歧视研究评估药物的诱发感受性刺激的可能性（感觉）类似于另一种药物的感觉. In general, drugs within the same pharmacological class share comparable interoceptive stimulus and are known to substitute for each other in the drug discrimination test.
When evaluating a new drug’s abuse potential, it is important to determine whether the testing drug shares discriminative properties with other known drugs of abuse. If Human Abuse Potential (HAP) studies are required later in the drug development process, information from the drug discrimination study may be used to determine the drug class experience required by the recreational drug user population selected for the study.
药物鉴别的典型研究设计
药品abuse liability studies should be conducted to GLP.
研究阶段
Each drug discrimination study includes the following phases:
- 压杆阶段训练老鼠用杠杆压力机来获得奖励（即蔗糖颗粒）。
- 双交替鉴别阶段在这项研究中，老鼠被训练来区分“药物”杠杆和“非药物”杠杆，以回应有区别的刺激。训练方案是连续两天服用训练药物，然后连续两天不服用药物，依此类推。
- The single alternation discrimination phase与前一阶段类似，但它提供了加剧难度，因为药物之间的测试和没有药物（例如盐水）每天交替。
- 预测试阶段（测试培训的最终阶段）以确认大鼠在用训练药物或药物（例如盐水）的药物（例如盐水）时预期的响应。
- First test sessionin which a dose response curve is obtained for the training drug.
- Final test sessionin which a dose response curve is obtained for the test drug.
选择训练药物
训练药物应尽可能与试验药物处于同一药理学类别，并应根据《管制物质法》进行安排。
For a test drug with a novel mechanism of action, a training drug that has a similar therapeutic indication or behavioral profile may be proposed. In some instances, multiple training drugs may be required or the test article itself may be used as the “training drug.”
Analyzing the Data
The following parameters should be evaluated:
The percentage of lever presses on the drug-associated lever.
如果药物相关的控制杆被按下。
- 超过80%=Full Generalization
- Between 20 and 80% =部分概括
- 低于20%=车辆适当响应
FDA指南指出，“如果试验药物对训练药物（一种已知的滥用药物）产生完全或部分概括，它可能有滥用的可能性。”
The Lever-Pressing Response Rate
The percentage of correct lever presses must be viewed in conjunction with the lever pressing response rate. Severe impairment of lever-pressing ability raises concerns about a test result’s reliability. Datasets in this article will demonstrate the impact of this.
选择杠杆识别以提供第一奖励
选择第一个提供奖励的杠杆的身份表明老鼠对辨别性线索的最初反应。
典型时间线
它通常需要22周才能完成药物歧视测试的生活中阶段。
兴奋剂、类阿片、镇静剂、致幻剂和大麻素示例
文章的最后部分探讨了内部数据的解释，与兴奋剂（Amphetamine＆Cocaine）;opioids（吗啡、丁丙诺啡、美沙酮）；benzodiazepines/sedatives（苯巴比妥、戊巴比妥、咪达唑仑），致幻剂(ketamine, PCP) and大麻素.
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