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: 8605161
• 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 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8605161
• 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.

描述（由申请人提供）：尽管最近可用于治疗全身真菌疾病的抗真菌药物的数量增加，但发病率和死亡率仍然很大；注意到，美国主要在免疫功能低下的患者中，浸润性念珠菌病（IC）是美国医院血流感染的第四大原因，并且IC与所有血液感染中最高的原状死亡率有关（CA。40％）。鉴于IC的惨淡结果，越来越多地考虑了抗真菌剂的组合。然而，在剂量选择，剂量分馏，预测性PD指数（PDI）和抗生物后抗生物效应（PAE）方面，针对抗真菌药的已建立和新型组合的药效（PD）特性在与治疗功效和宿主毒性方面有关。该研究项目的主要目的是表征IC的中性粒细胞鼠模型中抗真菌剂的固定和新型组合的PD特性，旨在超越当前研究和治疗范围的IC的新见解和进步，这通常是单一基于单一药物的。为了启用体内PD研究，我们通过自组装聚合物与其他抗真菌剂与其他抗真菌剂的组合交付（共递送）取得了令人兴奋的进步，从而实现了可溶性，安全性，稳定性和协同作用的要求，现在可以通过组合抗抗癌药物的相同动作来实现这一目标。我们假设AMB和5-氟胞嘧啶（5-FC）静脉内递送一起递送，将发挥有效的抗真菌活性，在口服5-FC后观察到5-FC低或没有转化为5-Fluorouracil（5-FU），导致骨髓骨髓毒性降低。我们假设AMB和17-乙酰胺-17-甲氧基甲霉素（17-AAG），一种热休克蛋白90（HSP90）抑制剂，将发挥有效的肾脏毒性抗真菌活性。特定目的：（1）表征胶束AMB和5-FC的PK，IC的中性粒细胞鼠模型中的抗真菌活性，以及​​单剂量和多剂量（剂量分馏）方案的毒性：PAE；预测性PDI（用于最大的抗真菌功效和最佳剂量方案）；和血液相对于口服5-FC。 （2）表征胶束AMB和17-AAG的PK，在IC的中性鼠模型中，抗真菌活性，单剂量和多剂量方案中的毒性：PAE；预测PDI；以及肾脏和肝毒性。 （3）表征了胶束AMB，5-FC和胶束17- AAG的PK，在IC的中性粒细胞鼠模型中，抗真菌活性，以及​​单剂量和多剂量方案的毒性：PAE；预测PDI；血液学;肾脏毒性；和主要器官的组织病理学。