Influenza and Emerging Infectious Diseases

这一新项目研究的病原体中最重要的是流感病毒，包括传统季节性流感的病原体以及禽流感（H5 N1）病毒的新威胁。使用现有或新开发的策略治疗感染的新方法是LIR临床研究部门这一重要新项目的主要重点。该项目的第一个主要举措是与退伍军人事务部（DVA）和国防部合作。该多中心方案的目的是确定是否可以使用新的药代动力学方法来延长奥司他韦的有效半衰期，奥司他韦是美国和其他地方用于治疗季节性流感的主要许可口服抗病毒药物，也是全球范围内相对短缺的药物。具体而言，该方案检查了两种不同剂量的口服丙磺舒（一种已知影响某些药物的肾分泌的许可的促尿酸药物）对隔日口服奥司他韦常规预防剂量与每日单独口服奥司他韦的相对药代动力学的影响。该方案在美国4个中心的53名65岁以上和65岁以下的正常志愿者中进行：两个DVA中心（包括作为牵头中心的Palo Alto Health Care系统），一个DOD中心和NIH临床中心。奥司他韦加丙磺舒的药代动力学进行了分析，并显示了剂量依赖性的有利影响后，前者的谷浓度和曲线下面积。在丙磺舒每日4次给药方案下，这些参数与奥司他韦单独每日给药无统计学差异，表明丙磺舒可能有助于在药物供应有限的情况下扩大奥司他韦的供应。 奥司他韦有效治疗严重季节性流感病例的能力可能有限，关于其治疗人类禽流感病例的效用的知识主要是轶事。出于这些原因，我们进行了三项临床试验，重点是人类流感的治疗。其中一项是在东南亚的研究合作者网络内进行的II期双盲随机临床试验，该试验比较了高剂量与标准剂量奥司他韦治疗严重流感和禽流感的相对疗效。这一审判目前仍在受影响国家进行。第二项是I期双盲、安慰剂对照、剂量递增研究，旨在评估一种新型静脉注射抗流感药物帕拉米韦在健康志愿者受试者中的相对安全性和耐受性。本试验在临床中心启动，但随后主要由申办者通过临床研究组织完成。该试验的数据目前正在分析和准备发表。第三项试验是一项第二阶段疫苗剂量探索试验研究，目的是开发一种抗甲型流感（H5 N1）静脉注射超免疫球蛋白制剂，该制剂可能用于治疗人类禽流感病例。这项试验的主要目的是确定最佳的疫苗接种策略，以获得高滴度的抗流感H5 N1抗体的健康志愿者使用许可的H5 NI疫苗。入组了4个队列：前三组（n= 75名志愿者）在几个月内接受了四剂90、120或180微克的H5 N1疫苗，而第四组（n= 51名志愿者）接受了两剂180微克的疫苗。所有队列的数据仍在分析中，但初步结果是1）H5 N1疫苗的超免疫是安全的，2）相对较高的接种者可以提高相对较高的滴度（滴度为1：80或更高）的免疫球蛋白，但疫苗剂量与接种频率的优化可能仍需要进一步研究。 除了这些试验外，我们还进行了一项新的鼻腔给药药物的研究，该药物对多种呼吸道病毒（包括流感）具有潜在的抗病毒活性。在该I期双盲、安慰剂对照、剂量递增研究中，评价局部鼻用Poly-ICLC（聚肌苷酸和聚胞苷酸的合成dsRNA链）的安全性和耐受性，正常志愿者接受递增剂量的该生物反应调节剂，以确定其经鼻给药时的安全性以及测量其给药的局部和全身免疫学效应。该试验目前正在进行中，最终数据分析预计将在未来6-8个月内开始。 最后，除了上述临床试验外，我们继续每年监测因2001年10月炭疽袭击而接触炭疽的一部分患者的临床和心理状况和健康状况， 以及维持一个开放的临床协议，以研究可能因意外或职业接触而发生的额外炭疽接触。

Foremost among the pathogens under study in this new project is the influenza virus, including both the agents of conventional seasonal influenza as well as the emerging threat of avian (H5N1) virus. Novel means to treat infection with either agent using existing or newly developed strategies are a primary focus of this important new project within the Clinical Research Section of the LIR. The first major initiative undertaken in this project has been a collaborative protocol undertaken with the Department of Veterans Affairs (DVA) as well as the Department of Defense. The goal of this multi-center protocol was to determine if novel pharmacokinetic means could be used to extend the useful half-life of oseltamivir, the major licensed oral antiviral drug used to treat seasonal influenza in the United states and elsewhere and also a drug in comparatively short supply on a global scale. Specifically, the protocol examined the effect of two different doses of oral probenecid, a licensed uricosuric agent known to affect the renal secretion of certain drugs, on the relative pharmacokinetics of conventional prophylactic doses of oral oseltamivir administered every other day compared to daily oral oseltamivir alone. This protocol was conducted in 53 normal volunteers above and below 65 years of age at 4 centers in the United States: two DVA sites (including the Palo Alto Health Care system as lead center), one DOD site, and the NIH Clinical Center. The pharmacokinetics of oseltamvir plus probenecid were analyzed and showed a dose-dependent favorable effect of the latter upon both the trough and area-under-the-curve concentrations of the former. At the schedule of four times daily dosing with probenecid, these parameters were not statistically different from daily dosing of oseltamivir alone, suggesting that probenecid might be useful in extending the supply of oseltamivir in a situation of limited drug supply. The ability of oseltamivir to treat effectively severe cases of seasonal influenza may be limited, and knowledge of its utility in treating human cases of avian influenza is largely anecdotal. For these reasons we undertook three clinical trials focused on the therapeutics of human influenza. One is a phase II double-blinded, randomized clinical trial conducted within a network of research collaborators in Southeast Asia that is comparing the relative efficacy of high dose versus standard-dose oseltamivir for the treatment of severe influenza and avian influenza. This trial is presently still accruing in the affected countries. The second was a phase I double-blind, placebo-controlled, dose-escalating study to evaluate the relative safety and tolerability of a novel intravenous anti-influenza agent, peramivir, in healthy volunteer subjects. This trial was initiated at the Clinical Center but then largely completed by the sponsor through a Clinical Research Organization. Data from that trial are presently being analyzed and prepared for publication. The third trial is a phase II vaccine dose-finding pilot study for the development of an anti-influenza A (H5N1) intravenous hyper-immune globulin preparation of potential utility in the treatment of human cases of avian influenza. The primary objective of this trial was to determine the optimal vaccination strategy to achieve high titer anti-influenza H5N1 antibodies in healthy volunteers using the licensed H5NI vaccine. Four cohorts were enrolled: the first three (n= 75 volunteers) received four doses of either 90, 120, or 180 micrograms of H5N1 vaccine over several months, whereas the fourth cohort (n= 51 volunteers) received two doses of 180 micrograms. Data from all cohorts are still being analyzed, but preliminary findings are that 1) hyper-immunization with H5N1 vaccine is safe, and 2) comparatively high titer (titer of 1:80 or greater) immune globulin can be raised in a relatively high percentage of recipients, but optimization of vaccine dose versus frequency of administration might still need further study. In addition to these trials, we have also undertaken a study of a novel nasally-administered agent with potential antiviral activity against a variety of respiratory viruses, including influenza. In this phase I double-blind, placebo-controlled, dose-escalating study to evaluate the safety and tolerability of topical nasal Poly-ICLC (synthetic dsRNA strands of poly-inosinic and poly-cytidylic acids), normal volunteers are receiving escalating doses of this biologic response modifier to determine its safety when nasally administered as well as to measure both local and systemic immunologic effects of its administration. This trial is currently accruing and final data analysis is anticipated to begin within the next 6-8 months. Lastly, in addition to the clinical trials described above, we continue to monitor on a yearly basis the clinical and psychologic status and well-being of a subset of patients previously exposed to anthrax as a result of the October 2001 anthrax attack, as well as maintaining an open clinical protocol for the study of additional anthrax exposures that may occur through accidental or occupational exposures.