PHASE I AND II STUDIES OF INVESTIGATIONAL AMINOQUINOLINES

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。全世界疟疾的发病率和死亡率惊人，每年有3亿多例病例和1至200万人死亡。尽管这一问题具有压倒性的性质，但抗疟疾治疗仍面临严重困难。氯喹（Chloroquine， CQ）是40多年来最重要的一种疟疾，但现在由于氯喹耐药性在东南亚、南美和非洲稳步上升而受到损害。甲氟喹和氟苯三嗪等替代药物本身也受到东南亚，特别是泰国日益增加的耐药性的影响。奎宁和奎尼丁因其毒性和部分耐药性的出现而受到损害。此外，CQ是唯一已知可安全用于孕妇的抗疟药。基于所有这些原因，与CQ类似的对耐药寄生虫有活性的AQs将成为治疗疟疾的重要资产。如果这些化合物与CQ足够相似，它们可能同样是无毒的，因此可能是对四环素（不能给8岁以下的儿童或孕妇服用）和青蒿素（对狗产生小脑毒性，可能溶解怀孕小鼠和大鼠的胎儿）等替代品的重大改进。本研究是基于氨基喹啉（AQ-13）在体外对氯喹（CQ）敏感、CQ耐药、甲氟喹耐药和多重耐药恶性疟原虫有活性的研究；在恒河猴体内对抗一种类似间日疟原虫的cq敏感寄生虫（Cynomolgi）；以及松鼠猴体内抗cq抗性恶性疟原虫。该项目的具体目标是：1)在新奥尔良成年志愿者中确定研究性氨基喹啉（AQ-13）的安全性和药代动力学；2)明确AQ-13对马里成人无症状cq敏感恶性疟原虫感染的疗效和药代动力学；3)确定AQ-13对马里成人症状性氯喹耐药恶性疟原虫感染的疗效和药代动力学。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The worldwide incidence and mortality of malaria are overwhelming, with more than 300 million cases and 1-2 million deaths each year. Despite the overwhelming nature of this problem, antimalarial therapy is in serious difficulty. Chloroquine (CQ), which has been the single most important malarial for more than forty years, is now compromised by the steadily increasing prevalence of CQ resistance in Southeast Asia, South America and Africa. Alternative drugs such as mefloquine and halofantrine are themselves compromised by increasing resistance in Southeast Asia, especially Thailand. Quinine and quinidine are compromised by both their toxicity, and the emergence of partial resistance. In addition, CQ is the only antimalarial known to be safe for use in pregnant women. For all these reasons, AQs similar to CQ which were active against resistant parasites, would be a major asset in the treatment of malaria. If those compounds were similar enough to CQ, they might be similarly nontoxic, and could therefore be a major improvement over alternatives such as tetracycline (which cannot be given to children less than eight years of age or to pregnant women) and artemisinin (which produced cerebellar toxicity in dogs and may dissolve fetuses in pregnant mice and rats). This study is based on an investigational aminoquinoline (AQ-13) which is active against chloroquine (CQ)-susceptible, CQ resistant, mefloquine-resistant and multiply resistant P. falciparum in vitro; against a CQ-susceptible parasite similar to P. vivax in vivo in rhesus monekys (P. Cynomolgi); and against CQ-resistant P. falciparum in vivo in squirrel monkeys. The specific aims of this project are to: 1) define the safety and pharmacokinetics of an investigational aminoquinoline (AQ-13) among adult volunteers in New Orleans; 2) define the efficacy and pharmacokinetics of AQ-13 for asymptomatic CQ-susceptible P. falciparum infections in Maliam adults; and 3) define the efficacy and pharmacokinetics of AQ-13 for symptomatic chloroquine resistant P. falciparum infections in Malian adults.