PHASE I AND II STUDIES OF INVESTIGATIONAL AMINOQUINOLINES

研究性氨基喹啉的 I 期和 II 期研究

• 批准号: 7376249
• 负责人: Donald John Krogstad
• 金额: $ 8.33万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7376249
• 关键词: PHASE; II; STUDIES; INVESTIGATIONAL; AMINOQUINOLINES

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.

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。疟疾在世界范围内的发病率和死亡率令人难以抗拒，每年有3亿多例病例和100-200万人死亡。尽管这一问题具有压倒性的性质，但抗疟疾治疗仍处于严重困难之中。40多年来一直是最重要的单一疟疾的氯喹(CQ)，现在正受到东南亚、南美和非洲不断增加的CQ耐药性的影响。在东南亚，特别是泰国，甲氟喹和氟苯三胺等替代药物本身也受到越来越多的耐药性的影响。奎宁和奎尼丁因其毒性和出现部分耐药性而受到损害。此外，CQ是已知的唯一可安全用于孕妇的抗疟疾药物。由于所有这些原因，类似于CQ的AQS对抗药性寄生虫有效，将是治疗疟疾的主要资产。如果这些化合物与CQ足够相似，它们可能同样无毒，因此可能是对四环素(不能给8岁以下儿童或孕妇服用)和青蒿素(对狗产生小脑毒性，并可能溶解怀孕小鼠和大鼠的胎儿)等替代品的重大改进。本研究的基础是一种氨基喹啉(AQ-13)，它在体外对氯喹(CQ)敏感、CQ耐药、甲氟喹耐药和多重耐药的恶性疟原虫具有活性；在体内对恒河猴(P.Cynomolgi)体内对CQ敏感的类似间日疟原虫的寄生虫具有抗药性；在体内对CQ耐药的恶性疟原虫具有体内抗药性。该项目的具体目的是：1)确定一种氨基喹啉(AQ-13)在新奥尔良成年志愿者中的安全性和药代动力学；2)确定AQ-13对Maliam成人无症状的CQ敏感恶性疟原虫感染的疗效和药代动力学；以及3)确定AQ-13对马里成人氯喹抗药性恶性疟原虫感染的疗效和药代动力学。