Quantification of cerivastatin toxicity supports organismal performance assays as an effective tool during pharmaceutical safety assessment.
Quantification of cerivastatin toxicity supports organismal performance assays as an effective tool during pharmaceutical safety assessment.
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DOI：
10.1111/eva.12365
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发表时间：
2016-06
影响因子：
4.1
通讯作者：
Potts WK
中科院分区：
文献类型：
--
作者：
Gaukler SM;Ruff JS;Galland T;Underwood TK;Kandaris KA;Liu NM;Morrison LC;Veranth JM;Potts WK
药物开发中的一个主要问题是，在临床前和临床试验期间，不良反应仍未被发现，但后来在市场发布后，当处方给许多患者时，这些不良反应才被发现。我们开发了一种被称为有机体性能测定（OPA）的适应性测定，该测定通过利用远交野生小鼠（Mus musculus）来评估个体性能，这些小鼠被分配到暴露组或对照组，它们在半自然围栏内相互竞争资源。性能测量包括生殖成功，生存和男性竞争力。我们的目的是利用西立伐他汀（Baycol®，Bayer），一种已知具有不良反应的药物，作为阳性对照，以评估OPA作为临床前试验期间评价化合物安全性的潜在工具。小鼠暴露于西立伐他汀（约4.5 mg/kg/天）至成年早期。停止暴露，并将动物释放到半天然围栏中。在围栏内，与对照组相比，暴露于西立伐他汀的雌性动物的后代减少了25%，暴露于西立伐他汀的雄性动物的体重减少了10%，占据的领地减少了63%，后代减少了41%，死亡率增加了3倍。OPA检测到几种西立伐他汀诱导的不良反应，表明生态学和进化生物学中常用的适应性试验可能是药物开发期间安全性测试的额外工具。
A major problem in pharmaceutical development is that adverse effects remain undetected during preclinical and clinical trials, but are later revealed after market release when prescribed to many patients. We have developed a fitness assay known as the organismal performance assay (OPA), which evaluates individual performance by utilizing outbred wild mice (Mus musculus) that are assigned to an exposed or control group, which compete against each other for resources within semi‐natural enclosures. Performance measurements included reproductive success, survival, and male competitive ability. Our aim was to utilize cerivastatin (Baycol®, Bayer), a pharmaceutical with known adverse effects, as a positive control to assess OPAs as a potential tool for evaluating the safety of compounds during preclinical trials. Mice were exposed to cerivastatin (~4.5 mg/kg/day) into early adulthood. Exposure ceased and animals were released into semi‐natural enclosures. Within enclosures, cerivastatin‐exposed females had 25% fewer offspring and cerivastatin‐exposed males had 10% less body mass, occupied 63% fewer territories, sired 41% fewer offspring, and experienced a threefold increase in mortality when compared to controls. OPAs detected several cerivastatin‐induced adverse effects indicating that fitness assays, commonly used in ecology and evolutionary biology, could be useful as an additional tool in safety testing during pharmaceutical development.