Safety and Pharmacokinetic Profiles of Phosphorodiamidate Morpholino Oligomers with Activity against Ebola Virus and Marburg Virus: Results of Two Single-Ascending-Dose Studies

Two identical single-ascending-dose studies evaluated the safety and pharmacokinetics (PK) of AVI-6002 and AVI-6003, two experimental combinations of phosphorodiamidate morpholino oligomers with positive charges (PMOplus) that target viral mRNA encoding Ebola virus and Marburg virus proteins, respectively. Both AVI-6002 and AVI-6003 were found to suppress disease in virus-infected nonhuman primates in previous studies. AVI-6002 (a combination of AVI-7537 and AVI-7539) or AVI-6003 (a combination of AVI-7287 and AVI-7288) were administered as sequential intravenous (i.v.) infusions of a 1:1 fixed dose ratio of the two subcomponents. In each study, 30 healthy male and female subjects between 18 and 50 years of age were enrolled in six-dose escalation cohorts of five subjects each and received a single i.v. infusion of active study drug (0.005, 0.05, 0.5, 1.5, 3, and 4.5 mg/kg per component) or placebo in a 4:1 ratio. Both AVI-6002 and AVI-6003 were safe and well tolerated at the doses studied. A maximum tolerated dose was not observed in either study. The four chemically similar PMOplus components exhibited generally similar PK profiles. The mean peak plasma concentration and area under the concentration-time curve values of the four components exhibited dose-proportional PK. The estimated plasma half-life of all four components was 2 to 5 h. The safety of the two combinations and the PK of the four components were similar, regardless of the target RNA sequence.     

Understanding the Chronic Impacts of Oil Refinery Wastewater Requires Consideration of Sediment Contributions to Toxicity

Previous studies at an oil refinery in Saint John, New Brunswick, Canada, found a diminished fish community downstream of the effluent outfall that appeared to be associated with periodic low dissolved oxygen concentrations due to episodic discharges of contaminated transport vessel ballast water. This study was initiated after the ballast water was removed from the effluent to further investigate the potential causes of residual effects in the study stream, Little River. We used field caging of fish, laboratory bioassays, and chemical analysis of effluents and sediments from the field site to determine if the effluent or contaminated sediments were affecting the recovery of the fish community in Little River. The field studies suggested that exposed, caged fish were affected, displaying >40 % increases in liver sizes and increased liver detoxification enzyme activity (cytochrome P450 1A, CYP1A); however, similar responses were absent in laboratory exposures that used effluent only. Adding sediments collected from the vicinity of the refinery’s outfall to the laboratory bioassays reproduced some of the field responses. Chemical analyses showed high concentrations of PAHs in sediments but low concentrations in the effluent, suggesting that the PAHs in the sediment were contributing more to the impacts than the effluent. Application of effects-based monitoring is suggested as beneficial to identify impacts to fisheries where refinery effluents of this type are involved.     

Findings from a cluster randomised trial of unconditional cash transfers in Niger

Unconditional cash transfers (UCTs) are used as a humanitarian intervention to prevent acute malnutrition, despite a lack of evidence about their effectiveness. In Niger, UCT and supplementary feeding are given during the June–September “lean season,” although admissions of malnourished children to feeding programmes may rise from March/April. We hypothesised that earlier initiation of the UCT would reduce the prevalence of global acute malnutrition (GAM) in children 6–59 months old in beneficiary households and at population level. We conducted a 2‐armed cluster‐randomised controlled trial in which the poorest households received either the standard UCT (4 transfers between June and September) or a modified UCT (6 transfers from April); both providing 130,000 FCFA/£144 in total. Eligible individuals (pregnant and lactating women and children 6–<24 months old) in beneficiary households in both arms also received supplementary food between June and September. We collected data in March/April and October/November 2015. The modified UCT plus 4 months supplementary feeding did not reduce the prevalence of GAM compared with the standard UCT plus 4 months supplementary feeding (adjusted odds ratios 1.09 (95% CI [0.77, 1.55], p = 0.630) and 0.93 (95% CI [0.58, 1.49], p = 0.759) among beneficiaries and the population, respectively). More beneficiaries receiving the modified UCT plus supplementary feeding reported adequate food access in April and May (p < 0.001) but there was no difference in endline food security between arms. In both arms and samples, the baseline prevalence of GAM remained elevated at endline (p > 0.05), despite improved food security (p < 0.05), possibly driven by increased fever/malaria in children (p < 0.001). Nonfood related drivers of malnutrition, such as disease, may limit the effectiveness of UCTs plus supplementary feeding to prevent malnutrition in this context. Caution is required in applying the findings of this study to periods of severe food insecurity.