PDF(Pubmed)
Abstract：
Drug administration in preclinical rodent models is essential for research and the development of novel therapies. Compassionate administration methods have been developed, but these are mostly incompatible with water-insoluble drugs such as tamoxifen or do not allow for precise timing or dosing of the drugs. For more than two decades, tamoxifen has been administered by oral gavage or injection to CreERT2-loxP gene-modified mouse models to spatiotemporally control gene expression, with the numbers of such inducible models steadily increasing in recent years. Animal-friendly procedures for accurately administering tamoxifen or other water-insoluble drugs would, therefore, have an important impact on animal welfare. On the basis of a previously published micropipette feeding protocol, we developed palatable formulations to encourage voluntary consumption of tamoxifen. We evaluated the acceptance of the new formulations by mice during training and treatment and assessed the efficacy of tamoxifen-mediated induction of CreERT2-loxP-dependent reporter genes. Both sweetened milk and syrup-based formulations encouraged mice to consume tamoxifen voluntarily, but only sweetened milk formulations were statistically noninferior to oral gavage or intraperitoneal injections in inducing CreERT2-mediated gene expression. Serum concentrations of tamoxifen metabolites, quantified using an in-house-developed cell assay, confirmed the lower efficacy of syrup- as compared to sweetened milk-based formulations. We found dosing with a micropipette to be more accurate than oral gavage or injection, with the added advantage that the method requires little training for the experimenter. The new palatable solutions encourage voluntary consumption of tamoxifen without loss of efficacy compared to oral gavage or injections and thus represent a refined administration method.
摘要：
临床前啮齿动物模型中的药物管理对于研究和开发新疗法至关重要。体恤管理方法已经开发，但这些药物大多与他莫昔芬等水不溶性药物不相容，或者不允许药物的精确时机或剂量。二十多年来,他莫昔芬已通过口服灌胃或注射给CreERT2-loxP基因修饰的小鼠模型，以时空控制基因表达，随着近年来此类可诱导模型的数量稳步增加。准确施用他莫昔芬或其他水不溶性药物的动物友好程序，因此,对动物福利有重要影响。根据先前发布的微量移液管进料协议，我们开发了可口的配方来鼓励他莫昔芬的自愿消费.我们评估了小鼠在训练和治疗期间对新制剂的接受度，并评估了他莫昔芬介导的CreERT2-loxP依赖性报告基因诱导的功效。甜牛奶和糖浆配方都鼓励小鼠自愿食用他莫昔芬，但在诱导CreERT2介导的基因表达方面,只有甜味配方在统计学上不劣于口服灌胃或腹腔注射.他莫昔芬代谢物的血清浓度，使用内部开发的细胞测定法进行定量，证实了与甜味乳基配方相比，糖浆的功效较低。我们发现用微量移液管给药比口服灌胃或注射更准确，具有额外的优点，即该方法需要对实验者进行很少的培训。与口服灌胃或注射相比，新的可口解决方案鼓励他莫昔芬的自愿消费而不会损失功效，因此代表了一种完善的施用方法。
