Vitamin D as Supplemental Therapy for Pneumocystis Pneumonia

 描述(由申请人提供) 肺孢子虫肺炎(PCP)是艾滋病患者的主要机会性疾病。即使采用了高效的抗逆转录病毒疗法，PCP仍然是艾滋病的一个重要问题。目前，治疗PCP最有效的方法是甲氧苄啶联合磺胺甲恶唑(TMP-SMX)。不幸的是，许多患有PCP的艾滋病患者未能通过这种方案进行治疗。我们发现，全反式维甲酸(ATRA)联合8-氨基喹啉伯喹(PMQ)对小鼠和大鼠PCP的治疗效果与TMP-SMX相当。由于全反式维甲酸有一定的副作用，我们测试了维生素D，发现它与PMQ联合使用，能有效地抑制肺孢子虫的增殖。我们假设维生素D-PMQ组合可以优化成为治疗PCP的理想替代疗法。我们还假设，一些疗效较差的PCP药物，如阿托瓦酮和氨苯砜，如果与维生素D联合使用，其疗效可以得到改善。在这个拟议的项目中，将确定治疗PCP的维生素D和PMQ的最佳剂量。维生素D联合PMQ、氨苯砜或阿托瓦酮可用于预防PCP的假设也将得到验证。为了探索这些新疗法的潜在机制，我们将研究维生素D通过减轻肺部炎症、促进肺泡巨噬细胞(AM)产生抗菌肽以及恢复AM的数量和功能来增强宿主防御的可能性。拟议的研究将证明维生素D与伯氨喹、氨苯砜或阿托瓦酮联合治疗PCP是有效的，并为新方案的人体临床试验奠定基础。这种新疗法将消除与TMP-SMX相关的磺胺类药物过敏的潜在风险，使无法耐受TMP-SMX的患者能够得到有效治疗。

 DESCRIPTION (provided by applicant) Pneumocystis pneumonia (PCP) is a major opportunistic disease in patients with AIDS. Even with the highly active anti-retroviral therapy, PCP remains a significant problem in AIDS. At present, the most effective treatment for PCP is the combination of trimethoprim and sulfamethoxazole (TMP-SMX). Unfortunately, many AIDS patients with PCP fail therapy with this regimen. We have found that all-trans retinoic acid (ATRA) in combination with primaquine (PMQ), which is an 8-aminoquinoline, was as effective as TMP-SMX for treatment of PCP in both mice and rats. Since ATRA has some adverse effects, we tested vitamin D and found that in combination with PMQ, it is effective in suppressing the proliferation of Pneumocystis. We hypothesize that the vitamin D-PMQ combination can be optimized to become an ideal alternative treatment for PCP. We also hypothesize that the efficacy of some less effective drugs for PCP, such as atovaquone and dapsone, can be improved if they are used in combination with vitamin D. In this proposed project, the optimal doses of vitamin D and PMQ for PCP therapy will be determined. The hypothesis that vitamin D in combination with PMQ, dapsone, or atovaquone can be used for prophylaxis of PCP will also be examined. To explore the underlying mechanism of these novel therapies, the possibility that vitamin D strengthens host defense by reducing lung inflammation, promoting the production of antimicrobial peptides by alveolar macrophages (AMs), and restoring the number and function of AMs will be examined. The proposed studies will prove that the combination of vitamin D and primaquine, dapsone, or atovaquone is effective for treatment of PCP and establish the foundation for human clinical trials of the new regimen. The new therapy will eliminate the potential risk of sulf drug hypersensitivity associated with TMP- SMX, allowing patients who cannot tolerate TMP-SMX to be effectively treated.