Laboratory training and experience for an undergraduate

项目摘要 迫切需要开发预防癌症患者心脏毒性的方法， 用蒽环类药物治疗，蒽环类药物是治疗癌症的一类重要药物（例如阿霉素）。 蒽环类药物治疗相关的心脏毒性是一个严重影响患者护理的主要临床问题， 也限制了剂量和使用。超过四分之一的接受阿霉素治疗的患者发生显著的心脏病， 发病率，这种影响已被证明是剂量依赖性的。在多项临床前研究中，我们和其他人 已经确定了低剂量外源性一氧化碳（CO）在蒽环类药物中的治疗潜力 心脏毒性预防，包括保护心肌细胞免于细胞死亡， 心血管健康 迄今为止，吸入的CO气体（iCO）和与载体分子结合的CO（CORM）已经成为治疗的模式。 在大多数动物和所有研究CO潜在获益的临床研究中， 然而，iCO和CORMS预计不会成为药学上可接受且可行的治疗选择 由于使用iCO时，存在压缩CO气瓶的意外暴露风险，以及 难以控制剂量，以及CORM、载体分子毒理学、稳定性和CO释放 这些特点已被证明是发展的重大障碍。新型口服CO药物HBI-002 产品，是为了克服这些障碍，使使用CO，以防止心脏毒性， 蒽环类药物的使用。与所有药物一样，活性药物浓度的评估 在感兴趣的组织中的成分（API）是关键的。尽管存在吸入CO的组织中的数据，但不存在吸入CO的组织中的数据。 HBI-002，考虑到iCO的剂量通常很高，吸入CO的数据可能不适用 在组织分布研究中给出。基于这些原因，拟议项目的目标是确定 口服HBI-002药物产品给药后CO暴露的组织水平和药代动力学。

PROJECT SUMMARY There is an urgent need for the development of approaches to prevent cardiotoxicity in cancer patients being treated with anthracyclines, an important class of drugs in the treatment of cancer (e.g. doxorubicin). Anthracycline treatment-related cardiotoxicity is a major clinical problem that severely impacts patient care and also limits dose and usage. More than a quarter of patients who receive doxorubicin develop significant cardiac morbidity, and this effect has been shown to be dose dependent. In multiple preclinical studies, we and others have defined the therapeutic potential of low-dose exogenous carbon monoxide (CO) in anthracycline cardiotoxicity prevention, including protecting the cardiomyocyte from cell death and maintaining overall cardiovascular health. To date, inhaled CO gas (iCO) and CO bound to carrier molecules (CORMs) have been the modalities of choice in the majority of animal and in all the clinical studies carried out to study the potential benefit of CO. However, iCO and CORMS are not expected to be pharmaceutically acceptable and viable therapeutic options due to, with iCO, the risk of inadvertent exposure from the presence of compressed CO cylinders as well as difficulties in controlling dosing and, with CORMs, carrier molecule toxicology, stability, and CO release characteristics that have proven to be a substantial barrier to development. HBI-002, the novel oral CO drug product, was developed to overcome these barriers and enable the use of CO to prevent cardiotoxicity from anthracycline use. As with all drugs, the assessment of the concentration of the active pharmaceutical ingredient (API) in tissue of interest is critical. Although data exist in tissue with inhaled CO, no data exist with HBI-002, and the data with inhaled CO may not be applicable given the typically high doses of iCO that are given in tissue distribution studies. For these reasons, the objective of the proposed project is to determine tissue levels and pharmacokinetics of CO exposure after oral HBI-002 drug product dosing.