Co-Delivery of Antifungal Agents: Toxicity and Efficacy in Invasive Candidiasis

抗真菌药物的联合给药：侵袭性念珠菌病的毒性和功效

• 批准号: 8786047
• 负责人: Glen S. Kwon
• 金额: $ 37.63万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-15 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8786047
• 关键词: Amphotericin B; Animal Model; Antibiotics; Antifungal Agents; Antifungal Therapy; Area; Azoles; Blood; Bone Marrow; Bone Marrow Suppression; Candida albicans; Candidiasis; Cells; Clinical; Clinical Trials; Communicable Diseases; Cytosine; Development; Disease; Dose; Dose Fractionation; Drug Administration Routes; Drug Combinations; Drug Delivery Systems; Drug Kinetics; Evaluation; Extracellular Fluid; Flucytosine; Fluorouracil; Goals; HSP 90 inhibition; Health; Heat-Shock Proteins 90; Hematology; Hepatic; Histopathology; Human; Immunocompromised Host; In Vitro; Infection; Intravenous; Investigation; Kidney; Life; Macrolides; Micelles; Modeling; Morbidity - disease rate; Mus; Mycoses; Oral; Organ; Outcome; Outcomes Research; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Polyenes; Polymers; Predisposition; Property; Rattus; Regimen; Relative (related person); Research Project Grants; Route; Safety; Scientist; Sepsis; Series; Serum; Solubility; Specialist; Sterility; Stream; Study of serum; Therapeutic Studies; Time; Tissues; Toxic effect; Treatment Efficacy; Treatment Protocols; United States; base; clinical practice; drug development; experience; fungus; in vivo; indexing; inhibitor/antagonist; insight; killings; mortality; nanocarrier; novel; prototype; success

DESCRIPTION (provided by applicant): Despite recent increase in the number of antifungal agents available for the treatment of systemic fungal diseases, morbidity and mortality are substantial; noting that invasive candidiasis (IC) is the fourth most common cause of nosocomial bloodstream infection in the United States chiefly among immunocompromised patients and that IC is associated with the highest crude mortality of all bloodstream infections (ca. 40%). Given the dismal outcomes for IC, combination of antifungal agents is increasingly being considered. However, pharmacodynamic (PD) properties for established and novel combinations of antifungal agents are ill-defined in terms of dose selection, dose fractionation, predictive PD index (PDI), and post-antibiotic effect (PAE) in relation to treatment efficacy and host toxicity. The major goal of this research project is to characterize the PD properties of established and novel combinations of antifungal agents in a neutropenic murine model of IC, aiming for novel insights and progress in IC beyond the present scope of research and therapy, which is usually single agent-based. Towards enabling in vivo PD studies, we made exciting progress in combination delivery (co-delivery) of amphotericin B (AmB) with other antifungal agents via self-assembled polymers, fulfilling requirements in solubility, safety, stability, and synergy, which ca now be achieved by the coincident action of combination antifungal agents administered simultaneously. We hypothesize that AmB and 5-fluoro- cytosine (5-FC) delivered together intravenously will exert potent antifungal activity, with low or no conversion of 5-FC into 5-fluorouracil (5-FU), observed after oral 5-FC, resulting in decreased bone marrow toxicity. We hypothesize that AmB and 17-allylamino-17-demethoxygeldanamycin (17-AAG), a heat shock protein 90 (Hsp90) inhibitor, will exert potent antifungal activity with low renal toxicity. Specifc Aims: (1) To characterize PK of micellar AmB and 5-FC, antifungal activity in a neutropenic murine model of IC, and toxicity in single and multiple dose (dose fractionation) regimens: PAE; predictive PDI (for maximum antifungal efficacy and optimal dosing regimen); and hematology relative to oral 5-FC. (2) To characterize PK of micellar AmB and 17-AAG, antifungal activity in a neutropenic murine model of IC, and toxicity in single and multiple dose regimens: PAE; predictive PDI; and renal and hepatic toxicity. (3) To characterize PK of micellar AmB, 5-FC, and micellar 17- AAG, antifungal activity in a neutropenic murine model of IC, and toxicity in single and multiple dose regimens: PAE; predictive PDI; hematology; renal toxicity; and histopathology in major organs.

描述（由申请人提供）：尽管最近可用于治疗全身性真菌病的抗真菌药物的数量有所增加，但发病率和死亡率仍然很高；指出侵袭性念珠菌病 (IC) 是美国医院血流感染的第四大常见原因，主要发生在免疫功能低下的患者中，并且 IC 与所有血流感染中最高的粗死亡率相关（约 40%）。鉴于 IC 的惨淡结果，人们越来越多地考虑联合使用抗真菌药物。然而，已建立的和新型抗真菌药物组合的药效学 (PD) 特性在剂量选择、剂量分割、预测性 PD 指数 (PDI) 以及与治疗功效和宿主毒性相关的抗生素后效应 (PAE) 方面尚不明确。该研究项目的主要目标是在中性粒细胞减少性 IC 小鼠模型中表征已建立的和新型抗真菌药物组合的 PD 特性，旨在超越目前通常基于单一药物的研究和治疗范围，在 IC 方面获得新的见解和进展。为了实现体内PD研究，我们在通过自组装聚合物联合递送（共同递送）两性霉素B（AmB）与其他抗真菌药物方面取得了令人兴奋的进展，满足了溶解度、安全性、稳定性和协同作用方面的要求，现在可以通过同时给药的组合抗真菌药物的一致作用来实现这些要求。我们假设，AmB 和 5-氟胞嘧啶 (5-FC) 一起静脉注射将发挥有效的抗真菌活性，口服 5-FC 后观察到，5-FC 很少或没有转化为 5-氟尿嘧啶 (5-FU)，从而导致骨髓毒性降低。我们假设 AmB 和 17-allylamino-17-demethoxygeldanamycin (17-AAG)（一种热休克蛋白 90 (Hsp90) 抑制剂）将发挥有效的抗真菌活性，且肾毒性较低。具体目标： (1) 表征胶束 AmB 和 5-FC 的 PK、IC 中性粒细胞减少小鼠模型中的抗真菌活性，以及​​单剂量和多剂量（剂量分割）方案中的毒性：PAE；预测性 PDI（最大抗真菌功效和最佳给药方案）；和与口服 5-FC 相关的血液学。 (2) 表征胶束 AmB 和 17-AAG 的 PK、IC 中性粒细胞减少小鼠模型中的抗真菌活性以及单剂量和多剂量方案的毒性：PAE；预测性 PDI；以及肾和肝毒性。 (3) 表征胶束 AmB、5-FC 和胶束 17-AAG 的 PK、IC 中性粒细胞减少小鼠模型中的抗真菌活性以及单剂量和多剂量方案中的毒性：PAE；预测性 PDI；血液学;肾毒性；和主要器官的组织病理学。