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

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

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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（由适用提供）：肺炎孢子菌是一种真菌，在人类中导致肺炎肺炎肺炎（PCP），这仍然是与艾滋病患者相关的领先机会感染，即使在高度活跃的抗抗病毒治疗时代也是如此。 PCP越来越多地针对新的患有潜在慢性疾病状态的患者组，例如接受抗TNF疗法，其他免疫抑制剂以及潜在的慢性疾病（例如慢性阻塞性肺疾病（COPD））的患者。甲氧苄啶 - 磺胺甲恶唑（TMP-SMX）的联合疗法仍然是当今使用的标准预防和治疗方式，几乎没有其他治疗方法。在编码基因的P. jirovecii二氢蛋白酶合酶中，已经发现了与磺胺甲恶唑耐药性相关的突变的证据。因此，至关重要的是要开发抗PCP治疗的新方法。在该提案中，我们将基于以前的观察结果，即一氧化氮（NO）发电机略微酸化的亚硝酸盐（A-NO2-）可有效防止肺炎囊肿的体外生物膜的形式，并改善了标准悬浮培养物中的生存能力。在狗和大鼠中进行的毒理学研究以及I期人类试验表明，A-NO2-分别以最低19-20 mg/kg的剂量耐受性，具有最小的副作用，这可以很好地翻译这些努力。我们建议评估3种不同剂量的PCP治疗和预防小鼠模型的2种不同的递送模式，以确定减少真菌肺伯良的最有效的给药途径和治疗时间。最初的免疫学研究将指导进一步的机械实验，以确定这种新替代药物的作用方式。