Laboratory training and experience for an undergraduate

项目总结 迫切需要开发预防癌症患者心脏毒性的方法 使用治疗癌症的一类重要药物--蒽环类药物(如阿霉素)。 与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和 还限制了剂量和用法。在接受阿霉素治疗的患者中，超过四分之一的患者出现明显的心脏病 发病率，而且这种影响已被证明是剂量依赖的。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 预防心脏毒性，包括保护心肌细胞不受细胞死亡的影响，并保持整体 心血管健康。 到目前为止，吸入的CO气体(ICO)和与载体分子(球茎)结合的CO一直是 在大多数动物和为研究一氧化碳的潜在益处而进行的所有临床研究中都有选择。 然而，预计ICO和球茎不是药学上可接受和可行的治疗选择。 由于ICO存在因存在压缩的CO钢瓶而意外暴露的风险 难以控制剂量和球茎载体分子毒理学、稳定性和CO释放 已被证明是发展的重大障碍的特征。新型口服一氧化碳药物HBI-002 产品的开发是为了克服这些障碍，并使一氧化碳的使用能够防止来自 使用蒽环类药物。与所有药物一样，活性药物浓度的评估 感兴趣组织中的成分(API)至关重要。尽管在吸入CO的组织中存在数据，但没有数据存在于 HBI-002，考虑到通常高剂量的ICO，吸入CO的数据可能不适用 在组织分布研究中给出。出于这些原因，拟议项目的目标是确定 口服HBI-002药物产品后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.