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An innovative treatment for Pneumocystis pneumonia

肺孢子菌肺炎的创新治疗方法

基本信息

批准号：
8873445
负责人：
DANIEL J. HASSETT
金额：
$ 7.9万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-15 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8873445
关键词：
Acquired Immunodeficiency Syndrome Adverse effects Adverse event Anti-Tumor Necrosis Factor Therapy Blood Pressure Breathing Burkholderia Canis familiaris Chronic Chronic Disease Clindamycin Clinical Combined Modality Therapy Cyanides Cytochrome bc1 Complex Dihydropteroate Synthase Dizziness Dose Drops Drosophila chb protein Epithelial Cells Food Preservatives Future Gene Targeting Genes Highly Active Antiretroviral Therapy Human Immune Immunologics Immunosuppressive Agents In Vitro Infection Lung Lung diseases Maximum Tolerated Dose Meat Methemoglobin Methemoglobinemia Microbial Biofilms Modality Modeling Mus Mutation New Agents Nitric Oxide Nitrites No-Observed-Adverse-Effect Level Opportunistic Infections Patients Pentamidine Pharmaceutical Preparations Phase Pneumocystis Pneumocystis carinii Pneumocystis carinii Pneumonia Poisoning Primaquine Production Prophylactic treatment Rattus Resistance Resistance development Rodent Model Route Staphylococcus aureus Sulfamethoxazole Suspension Culture TNF gene Therapeutic Time Toxicology Translations Trimethoprim-Sulfamethoxazole alternative treatment atovaquone chemotherapeutic agent fungus healthy volunteer in vivo innovation killings methicillin resistant Staphylococcus aureus mouse model mucoid novel novel strategies pathogen phase 1 study prevent prophylactic public health relevance research study

项目摘要

DESCRIPTION (provided by applicant): Pneumocystis jirovecii is a fungus that causes Pneumocystis pneumonia (PCP) in humans which remains a leading opportunistic infection associated with AIDS patients, even in the era of Highly Active Anti-Retroviral Therapy (HAART). PCP increasingly targets new groups of patients with underlying chronic disease states, such as patients receiving anti-TNF therapy, other immunosuppressive agents and with underlying chronic diseases such as Chronic Obstructive Pulmonary Disorder (COPD). The combination therapy of trimethoprim- sulfamethoxazole (TMP-SMX) remains the standard prophylactic and therapeutic modality in use today with few alternative treatments. Evidence for mutations associated with resistance to sulfamethoxazole has been identified in the P. jirovecii dihydropteroate synthase encoding gene. It is thus critical that new approaches to anti-PCP therapy be developed. In this proposal, we will build on our previous observations that slightly acidified nitrite (A-NO2-), a nitric oxide (NO) generator, was effective in preventing the formatio of in vitro biofilms by Pneumocystis carinii and decreased viability in standard suspension cultures. Ongoing toxicology studies in dogs and rats and Phase I human trials revealed A-NO2- was well tolerated at doses up to 19-20 mg/kg, respectively, with minimal side effects, which bodes well for translation of these efforts. We propose to evaluate 2 different delivery modes for A-NO2- in therapeutic and prophylaxis mouse models of PCP at 3 different doses to determine the most effective administration route and treatment times that reduce fungal lung burdens. Initial immunological studies will guide further mechanistic experiments to determine the mode of action of this new alternative agent.

描述（由申请人提供）：耶氏肺孢子菌是一种引起人类肺孢子虫肺炎（PCP）的真菌，即使在高效抗逆转录病毒疗法（HAART）时代，它仍然是与艾滋病患者相关的主要机会性感染。 PCP 越来越多地针对具有潜在慢性疾病状态的新患者群体，例如接受抗 TNF 治疗、其他免疫抑制剂以及患有慢性阻塞性肺疾病 (COPD) 等潜在慢性疾病的患者。甲氧苄啶-磺胺甲恶唑 (TMP-SMX) 联合疗法仍然是当今使用的标准预防和治疗方式，几乎没有替代疗法。已在 P. jirovecii 二氢蝶酸合酶编码基因中鉴定出与磺胺甲恶唑耐药性相关的突变证据。因此，开发新的抗 PCP 治疗方法至关重要。在本提案中，我们将基于我们之前的观察结果，即微酸化亚硝酸盐 (A-NO2-)，一种一氧化氮 (NO) 发生器，可有效防止卡氏肺囊虫体外生物膜的形成，并降低标准悬浮培养物中的活力。正在进行的狗和大鼠毒理学研究以及 I 期人体试验表明，A-NO2- 在高达 19-20 mg/kg 的剂量下具有良好的耐受性，副作用最小，这预示着这些努力的转化。我们建议在 PCP 治疗和预防小鼠模型中以 3 种不同的剂量评估 2 种不同的 A-NO2- 给药模式，以确定减少真菌肺负荷的最有效的给药途径和治疗时间。初步的免疫学研究将指导进一步的机制实验，以确定这种新的替代药物的作用方式。