An innovative treatment for Pneumocystis pneumonia

 描述(由申请人提供)：吉罗维西氏肺孢子虫是一种引起人类肺炎(PCP)的真菌，即使在高效抗逆转录病毒治疗(HAART)的时代，这种真菌仍然是与艾滋病患者相关的主要机会性感染。PCP越来越多地针对潜在慢性病状态的新患者群体，如接受抗肿瘤坏死因子治疗的患者、其他免疫抑制剂以及慢性阻塞性肺疾病(COPD)等潜在慢性病患者。甲氧苄氨嘧啶-磺胺甲恶唑(TMP-SMX)的联合治疗仍然是当今使用的标准预防和治疗方法，几乎没有替代疗法。已发现与磺胺甲恶唑耐药相关的突变证据，该突变与日本血吸虫二氢蝶呤合酶编码基因有关。因此，开发新的抗PCP治疗方法至关重要。在这项建议中，我们将建立在我们之前的观察结果的基础上，即微酸性亚硝酸盐(A-NO2-)，一种一氧化氮(NO)生成器，在防止卡氏肺孢子虫体外生物膜形成和标准悬浮培养中活力下降方面是有效的。正在进行的狗和大鼠毒理学研究和第一阶段人体试验显示，A-NO2-在剂量分别为19-20 mg/kg时耐受性良好，副作用最小，这对这些努力的转化是个好兆头。我们建议在三种不同剂量的PCP治疗和预防小鼠模型中评估A-NO2-的两种不同给药方式，以确定减少真菌肺负担的最有效给药途径和治疗次数。初步的免疫学研究将指导进一步的机械性实验，以确定这种新的替代药物的作用模式。

 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.