[Show abstract][Hide abstract] ABSTRACT: Lassa fever is an acute viral hemorrhagic illness; the virus is endemic in West Africa and also of concern with regard to bioterrorism. Transmission of Lassa virus between humans may occur through direct contact with infected blood or bodily secretions. Oral administration of the antiviral drug ribavirin is often considered for postexposure prophylaxis, but no systematically collected data or uniform guidelines exist for this indication. Furthermore, the relatively low secondary attack rates for Lassa fever, the restriction of the area of endemicity to West Africa, and the infrequency of high-risk exposures make it unlikely that controlled prospective efficacy trials will ever be possible. Recommendations for postexposure use of ribavirin can therefore be made only on the basis of a thorough understanding and logical extrapolation of existing data. Here, we review the pertinent issues and propose guidelines based on extensive review of the literature, as well as our experience in this field. We recommend oral ribavirin postexposure prophylaxis for Lassa fever exclusively for definitive high-risk exposures. These guidelines may also serve for exposure to other hemorrhagic fever viruses susceptible to ribavirin.
[Show abstract][Hide abstract] ABSTRACT: To determine: (1) the pharmacokinetics and safety of an investigational aminoquinoline active against multidrug-resistant malaria parasites (AQ-13), including its effects on the QT interval, and (2) whether it has pharmacokinetic and safety profiles similar to chloroquine (CQ) in humans.
Phase I double-blind, randomized controlled trials to compare AQ-13 and CQ in healthy volunteers. Randomizations were performed at each step after completion of the previous dose.
Tulane-Louisiana State University-Charity Hospital General Clinical Research Center in New Orleans.
126 healthy adults 21-45 years of age.
10, 100, 300, 600, and 1,500 mg oral doses of CQ base in comparison with equivalent doses of AQ-13.
Clinical and laboratory adverse events (AEs), pharmacokinetic parameters, and QT prolongation.
No hematologic, hepatic, renal, or other organ toxicity was observed with AQ-13 or CQ at any dose tested. Headache, lightheadedness/dizziness, and gastrointestinal (GI) tract-related symptoms were the most common AEs. Although symptoms were more frequent with AQ-13, the numbers of volunteers who experienced symptoms with AQ-13 and CQ were similar (for AQ-13 and CQ, respectively: headache, 17/63 and 10/63, p = 0.2; lightheadedness/dizziness, 11/63 and 8/63, p = 0.6; GI symptoms, 14/63 and 13/63; p = 0.9). Both AQ-13 and CQ exhibited linear pharmacokinetics. However, AQ-13 was cleared more rapidly than CQ (respectively, median oral clearance 14.0-14.7 l/h versus 9.5-11.3 l/h; p < or = 0.03). QTc prolongation was greater with CQ than AQ-13 (CQ: mean increase of 28 ms; 95% confidence interval [CI], 18 to 38 ms, versus AQ-13: mean increase of 10 ms; 95% CI, 2 to 17 ms; p = 0.01). There were no arrhythmias or other cardiac AEs with either AQ-13 or CQ.
These studies revealed minimal differences in toxicity between AQ-13 and CQ, and similar linear pharmacokinetics.