New chemotherapy regimens and biomarkers for Chagas disease

恰加斯病的新化疗方案和生物标志物

• 批准号: 9484015
• 负责人: IGOR C ALMEIDA
• 金额: $ 118.19万
• 依托单位: UNIVERSITY OF TEXAS EL PASO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-17 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9484015
• 关键词: Acute; Adult; Adverse drug event; Adverse event; Affect; Aftercare; Age; Animals; Antibodies; Antigens; Antioxidants; Antiparasitic Agents; Appearance; Benznidazole; Biological Markers; Blood; Cardiomyopathies; Chagas Disease; Chemotherapy-Oncologic Procedure; Child; Chronic; Chronic Phase; Classification; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Country; Data; Detection; Disease; Dose; Drug Combinations; Drug Kinetics; Evaluation; Failure; Frequencies; Gold; Heart; Heat-Shock Proteins 70; Infant; Infection; Inflammatory; Latin America; Lytic; Measures; Nifurtimox; Oxidative Stress; Parasitemia; Parasites; Patients; Peptide antibodies; Peptides; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Phase; Play; Polysaccharides; Population; Prognostic Marker; Proteins; Public Health; Reaction; Recombinant Proteins; Regimen; Reporting; Research Design; Role; Safety; Serologic tests; Serological; Serum; Symptoms; Techniques; Testing; Therapeutic; Thrombophilia; Treatment Protocols; Treatment outcome; Trypanosoma cruzi; Tumor stage; aptamer; chemotherapy; chronic infection; cohort; drug efficacy; early detection biomarkers; experience; follow-up; improved; novel; novel diagnostics; progression marker; response; seroconversion; standard care; success; therapy outcome; tool; treatment duration; treatment response

ABSTRACT Chagas disease is caused by the parasite, Trypanosoma cruzi, and affects millions of people in Latin America. Lately, Chagas disease has become an emerging worldwide public health issue due to globalization. Chagas disease has two phases: an initial acute phase, usually with nonspecific symptoms or asymptomatic, and a lifelong chronic phase, which is clinically silent or indeterminate in 60-70% of patients. However, 30-40% of chronic patients will eventually develop heart and/or digestive complications. Currently, the only approved drugs for treating Chagas disease are benznidazole (BZN) and nifurtimox (NFX). The efficacy of these drugs is variable and depends on the disease stage, drug dose, age of patients, and infecting T. cruzi strain(s). Treatment in the acute phase is effective with both drugs. However, the efficacy of these drugs in adults with chronic, long-established infections is significantly lower and variable. Moreover, the high rate of adverse events of these drugs has hampered their regular clinical use, thus <1% of patients are being treated. In this project, we propose to test four new dosing regimens of BZN and NFX. Our first hypothesis is that a lower frequency of BZN and NFX dosing, with standard or extended treatment duration, might have the same or better efficacy than the standard treatment regimens with these drugs, with fewer adverse events. Here, we plan to analyze current and novel host- and parasite-derived BMKs that have shown promising results in pilot, full clinical trials or in animal studies, providing a measure of disease state and cure. Thus, our second hypothesis is that in those patients that respond to BZN or NFX treatment the serum levels of one or more proposed BMKs will be significantly reduced or become negative within three years post-treatment. To test these two hypotheses, we propose two specific aims: Specific Aim 1: To determine the safety and efficacy of extended benznidazole or nifurtimox treatment regimens with lower dosing frequency. Specific Aim 2: To evaluate host- and parasite-derived biomarkers for the follow-up of Chagas disease chemotherapy. The information gained in this project would also allow for better-designed clinical trials with previously proposed drug combinations, in which BZN and NFX would play a central role.

抽象的 恰加斯病是由寄生虫克氏锥虫引起的，影响着拉丁美洲数百万人。 近年来，由于全球化，恰加斯病已成为一个新兴的全球公共卫生问题。恰加斯 疾病有两个阶段：最初的急性期，通常有非特异性症状或无症状； 终生慢性期，60-70% 的患者临床上无症状或不确定。然而，30-40% 慢性患者最终会出现心脏和/或消化系统并发症。目前，唯一获批的 治疗南美锥虫病的药物有苯并硝唑（BZN）和硝呋莫司（NFX）。这些药物的功效是 可变的，取决于疾病阶段、药物剂量、患者年龄和感染克氏锥虫菌株。 两种药物在急性期的治疗均有效。然而，这些药物对成人患者的疗效 慢性、长期存在的感染明显较低且变化多端。而且不良率高 这些药物的事件阻碍了它们的常规临床使用，因此只有<1%的患者正在接受治疗。在这个 项目中，我们建议测试 BZN 和 NFX 的四种新给药方案。我们的第一个假设是较低的 标准或延长治疗持续时间的 BZN 和 NFX 给药频率可能相同或相同 与这些药物的标准治疗方案相比，疗效更好，不良事件更少。在这里，我们 计划分析当前和新型宿主和寄生虫衍生的 BMK，这些 BMK 在试验中显示出有希望的结果， 完整的临床试验或动物研究，提供疾病状态和治疗的衡量标准。因此，我们的第二个 假设是，在那些对 BZN 或 NFX 治疗有反应的患者中，一种或多种的血清水平 拟议的 BMK 将在治疗后三年内显着减少或变为负值。测试 针对这两个假设，我们提出两个具体目标： 具体目标 1：确定 以较低的给药频率延长苯硝唑或硝呋莫司治疗方案。具体目标 2： 评估宿主和寄生虫衍生的生物标志物，用于恰加斯病化疗的随访。这 在该项目中获得的信息也将有助于更好地设计先前提出的临床试验 药物组合，其中 BZN 和 NFX 将发挥核心作用。