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: 10557245
• 负责人: IGOR C ALMEIDA
• 金额: $ 91.62万
• 依托单位: UNIVERSITY OF TEXAS EL PASO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557245
• 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; Disease; Dose; Drug Combinations; Drug Kinetics; Evaluation; Excretory function; Failure; Frequencies; Heart; Heat-Shock Proteins 70; Infant; Infection; Inflammatory; Latin America; Lytic; Measures; Nifurtimox; Oxidative Stress; Parasitemia; Parasites; Parasitology; Patients; Peptide antibodies; Peptides; Peripheral; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phase; Play; Polysaccharides; Population; Proteins; Public Health; Reaction; Recombinant Proteins; Regimen; Reporting; Research Design; Role; Safety; Serology; Serum; Symptoms; Testing; Therapeutic; Thrombophilia; Treatment Protocols; Treatment outcome; Trypanosoma cruzi; aptamer; chemotherapy; chronic infection; cohort; detection method; diagnostic tool; drug efficacy; early detection biomarkers; experience; follow-up; improved; novel; novel diagnostics; prognosis biomarker; 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 Chagas病是由Cruzi锥虫，锥虫引起的，并影响了拉丁美洲的数百万人。 最近，由于全球化，查加斯病已成为全球新兴的公共卫生问题。查加斯 疾病有两个阶段：初始急性期，通常具有非特异性症状或无症状，并且 终身慢性期在60-70％的患者中在临床上保持沉默或不确定。但是，30-40％ 慢性病患者最终会发展为/或消化并发症。目前，唯一的批准 治疗chagas疾病的药物是苯甲酸唑（BZN）和Nifurtimox（NFX）。这些药物的功效是 可变并取决于疾病阶段，药物剂量，患者年龄以及感染t. cruzi菌株的疾病。 两种药物的急性期治疗均有效。但是，这些药物在成年人中的功效 慢性，长期以来的感染显着较低和可变。此外，不利的速度很高 这些药物的事件阻碍了他们的定期临床用途，因此正在治疗<1％的患者。在这个 项目，我们建议测试BZN和NFX的四种新剂量方案。我们的第一个假设是较低 BZN和NFX剂量的频率，具有标准或延长的治疗持续时间，可能具有相同或 与这些药物的标准治疗方案相比，效力更好，不良事件较少。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Pilot中显示出令人鼓舞的结果， 完整的临床试验或动物研究中，提供了疾病状态和治愈的度量。因此，我们的第二个 假设是在那些对BZN或NFX治疗反应的患者中 拟议的BMK将在处理后三年内显着降低或变为负。测试 这两个假设，我们提出了两个具体目的：具体目的1：确定的安全性和功效 替代频率较低的苯甲酸唑或nifurtimox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，以进行chagas疾病化疗的随访。这 该项目中获得的信息还将允许使用先前提出的更好设计的临床试验 BZN和NFX将发挥核心作用的药物组合。

项目成果

A Branched and Double Alpha-Gal-Bearing Synthetic Neoglycoprotein as a Biomarker for Chagas Disease.

• DOI: 10.3390/molecules27175714
• 发表时间: 2022-09-05
• 期刊: Molecules (Basel, Switzerland)

New chemotherapy regimens and biomarkers for Chagas disease: the rationale and design of the TESEO study, an open-label, randomised, prospective, phase-2 clinical trial in the Plurinational State of Bolivia.

• DOI: 10.1136/bmjopen-2021-052897
• 发表时间: 2021-12-31
• 期刊: BMJ open
• 影响因子: 2.9
• 作者: Alonso-Vega C;Urbina JA;Sanz S;Pinazo MJ;Pinto JJ;Gonzalez VR;Rojas G;Ortiz L;Garcia W;Lozano D;Soy D;Maldonado RA;Nagarkatti R;Debrabant A;Schijman A;Thomas MC;López MC;Michael K;Ribeiro I;Gascon J;Torrico F;Almeida IC
• 通讯作者: Almeida IC