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: 8497027
• 负责人: Glen S. Kwon
• 金额: $ 35.37万
• 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 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8497027
• 关键词: 17-(Allylamino)-17-demethoxygeldanamycin; 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; 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; public health relevance; 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.

说明(申请人提供)：尽管最近可用于治疗系统性真菌疾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；注意到侵袭性念珠菌病(IC)是美国医院内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，而且IC与所有血流感染中最高的粗死亡率(约40%)有关。考虑到IC的悲惨结局，联合使用抗真菌药物正越来越多地被考虑。然而，现有的和新的抗真菌药物组合的药效学(PD)性质在剂量选择、剂量分级、预测性PD指数(PDI)和抗生素后效应(PAE)与治疗效果和宿主毒性方面定义不清。本研究项目的主要目标是在中性粒细胞减少的IC小鼠模型中表征已建立的和新的抗真菌药物组合的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，对IC有新的见解和进展。为了进行体内PD研究，我们通过自组装聚合物在两性霉素B(Amb)与其他抗真菌药物的联合传递(共传递)方面取得了令人振奋的进展，满足了现在可以通过同时给予联合抗真菌药物的联合作用来实现的溶解性、安全性、稳定性和协同性的要求。我们推测，AMB和5-氟胞嘧啶(5-FC)联合静脉给药将发挥强大的抗真菌活性，口服5-FC后，5-FC转化为5-FU的转化率很低或没有，从而降低骨髓毒性。我们推测，Amb和热休克蛋白90(Hsp90)抑制剂17-烯丙氨基-17-去甲氧基格尔达那霉素(17-AAG)将具有较强的抗真菌活性，且肾脏毒性较低。具体目的：(1)表征胶束Amb和5-FC的PK，在中性粒细胞减少的IC小鼠模型中的抗真菌活性，以及在单剂量和多剂量(剂量分级)方案中的毒性：PAE；预测性PDI(最大抗真菌效果和最佳剂量方案)；以及与口服5-FC相关的血液学。(2)研究胶束Amb和17-AAG的PK、在中性粒细胞减少的IC小鼠模型中的抗真菌活性以及单次和多次给药方案的毒性：PAE；预测性PDI；以及肝和肾毒性。(3)表征胶束Amb、5-FC和胶束17-AAG的PK、在中性粒细胞减少的IC小鼠模型中的抗真菌活性以及单次和多次给药方案的毒性：PAE、预测性PDI、血液学、肾脏毒性和主要器官的组织病理学。