Development of System for Treatment of Tuberculosis

结核病治疗系统的开发

• 批准号: 6337289
• 负责人: Takuji Tsukamoto
• 金额: $ 10万
• 依托单位: CHEMICA TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-05 至 2003-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6337289
• 关键词: Mycobacterium tuberculosis; amidases; antitubercular agents; chemical synthesis; drug design /synthesis /production; esterase; high performance liquid chromatography; human tissue; hydropathy; infrared spectrometry; isoniazid; mass spectrometry; microorganism disease chemotherapy; nuclear magnetic resonance spectroscopy; palmitates; rifamycins; slow release drug; tissue /cell culture; tuberculosis

Tuberculosis causes a staggering burden of mortality world-wide, killing 2 million people annually. To cure tuberculosis, prolonged therapy of at least 6 months is required, because antituberculosis drugs do not penetrate well into macrophages, which are a major reservoir of M. tuberculosis. To devise antituberculosis medications that will shorten the duration of therapy, we will use microparticles to target the delivery of enzyme-cleavable lipophilic derivatives of isoniazid and rifampin to infected macrophages. Once inside the macrophage, the microparticles degrade and release the lipophilic drugs, which are then transported across the M. tuberculosis cell envelope. Our specific aims are: 1. To synthesize and characterize palmitic acid derivatives of isoniazid and rifampin. 2. To determine the rates of esterase or amidase hydrolysis of these derivatives. 3. To evaluate the capacity of these derivatives to kill M. tuberculosis. If this proposal is successful, a phase II proposal will be submitted to perform additional studies to evaluate these agents combined with microparticles in cell culture systems in vitro and in animals. This project will explore the feasibility of a strategy that can be applied to the treatment of infection caused by many intracellular organisms, including viruses, fungi and parasites. PROPOSED COMMERCIAL APPLICATIONS: The technology we will develop in this program has the potential to significantly improve the treatment of diseases due to pathogens that reside in macrophages, such as tuberculosis and HIV infection. In the treatment of tuberculosis, targeted-delivery systems of enzyme- cleavable lipophilic drugs are presently not available. This strategy has the potential to increase the efficacy of treatment, reduce the dosage of drugs required, reduce side effects of treatment, improve patient compliance, and minimize development of drug resistance.

结核病在全世界造成了惊人的死亡负担，每年夺去 200 万人的生命。为了治愈结核病，需要至少6个月的长期治疗，因为抗结核药物不能很好地渗透到巨噬细胞中，而巨噬细胞是结核分枝杆菌的主要储存库。为了设计出缩短治疗时间的抗结核药物，我们将使用微粒将酶可裂解的异烟肼和利福平亲脂性衍生物靶向递送至受感染的巨噬细胞。一旦进入巨噬细胞，微粒就会降解并释放亲脂性药物，然后这些药物被转运穿过结核分枝杆菌细胞包膜。我们的具体目标是： 1.异烟肼和利福平棕榈酸衍生物的合成和表征。 2.测定这些衍生物的酯酶或酰胺酶水解速率。 3.评价这些衍生物杀灭结核分枝杆菌的能力。如果该提案成功，将提交第二阶段提案以进行额外的研究，以在体外和动物细胞培养系统中评估这些药物与微粒的结合。该项目将探索一种可应用于治疗许多细胞内生物（包括病毒、真菌和寄生虫）引起的感染的策略的可行性。拟议的商业应用：我们将在该计划中开发的技术有可能显着改善巨噬细胞中病原体引起的疾病的治疗，例如结核病和艾滋病毒感染。在结核病的治疗中，目前还没有酶可裂解亲脂性药物的靶向递送系统。该策略有可能提高治疗效果、减少所需药物剂量、减少治疗副作用、提高患者依从性并最大限度地减少耐药性的产生。

项目成果

The pedipump: development status of a new pediatric ventricular assist device.

足泵：新型儿科心室辅助装置的开发现状。

• DOI: 10.1097/01.mat.0000178211.70743.99
• 发表时间: 2005
• 期刊: ASAIO journal (American Society for Artificial Internal Organs : 1992)
• 作者: Duncan,BrianW;Dudzinski,DavidT;Noecker,AngelaM;Kopcak,MichaelW;Fukamachi,Kiyotaka;Ootaki,Yoshio;Chen,HMing;Chapman,PeterA;Smith,WilliamA
• 通讯作者: Smith,WilliamA

The PediPump: a new ventricular assist device for children.

PediPump：一种新型儿童心室辅助装置。

• DOI: 10.1111/j.1525-1594.2005.29088.x
• 发表时间: 2005
• 期刊: Artificial organs
• 影响因子: 2.4
• 作者: Duncan,BrianW;Lorenz,Markus;Kopcak,MichaelW;Fukamachi,Kiyotaka;Ootaki,Yoshio;Chen,HMing;Chapman,PeterA;Davis,StevenJ;Smith,WilliamA
• 通讯作者: Smith,WilliamA