Search

Fostemsavir, a prodrug of temsavir, is indicated for heavily treatment-experienced adults with multidrug-resistant HIV-1 infection, antiretroviral (ARV) intolerance, or safety considerations. Understanding drug-drug interactions (DDIs) is important in individuals taking fostemsavir with hormonal contraceptives or menopausal or gender-affirming hormonal therapies.Effect of temsavir (active moiety) on the pharmacokinetics of ethinyl estradiol (EE) and norethindrone (NET) was evaluated in an open-label, single-sequence, four-cycle, four-treatment study in 26 healthy female participants (study 206279, NCT02480881). Relevant ARV-contraceptive interaction studies and guideline recommendations were reviewed; that information was then applied to other contraceptive methods and hormone-based therapies to predict the impact of fostemsavir co-administration.Temsavir increased EE concentrations by 40% and had no effect on NET concentrations. Fostemsavir co-administration with hormone therapy is not expected to impact hormone treatment efficacy. Fostemsavir did not impact progestin; therefore, progestin-only and non-hormonal contraceptives will not be impacted by fostemsavir. Recommendations for co-administration of fostemsavir and hormonal contraceptives or menopausal or gender-affirming hormone therapies are based upon known and predicted DDIs, ensuring adequate hormonal concentrations to maintain the target effect.Applying the results of Study 206279 and other relevant ARV-contraceptive studies, we recommend that when co-administering fostemsavir with combined oral contraceptives (COCs) and other oestrogen-based therapies, EE dose should not exceed 30 μg or equivalent, and caution is advised in the case of individuals with risk factors for thromboembolic events. Other oestrogen-based therapies may be co-administered with fostemsavir, with monitoring of oestrogen concentrations and appropriate dose adjustments. No impact of fostemsavir on COC efficacy is expected.

The pharmacokinetics, elimination, and metabolism of fostemsavir (FTR), a prodrug of the HIV-1 attachment inhibitor temsavir (TMR), were investigated in healthy volunteers. FTR was administered with and without ritonavir (RTV), a protease inhibitor previously shown to boost TMR exposures. In vitro studies were also used to identify the enzymes responsible for the metabolism of TMR.Total recovery of the administered dose ranged from 78% to 89%. Approximately 44% to 58% of the dose was excreted in urine, 20%–36% in faeces, and 5% in bile, as TMR and metabolites. RTV had no effect on the recovery of radioactivity in any matrix.Compared to FTR alone, pre-treatment of subjects with RTV increased the exposure of TMR by ∼66% and reduced the exposure of plasma total radioactivity by ∼68%.The major route of TMR elimination was through biotransformation. TMR, M28 (N-dealkylation), and M4 (amide hydrolysis) were the major circulating components in plasma. Pre-treatment with RTV increased the amount of TMR present, decreased the amount of circulating M28, and M4 was unchanged.CYP3A4 metabolism accounted for 21% of the dose, forming multiple oxidative metabolites. This pathway was inhibited by coadministration of RTV. The pharmacokinetics, elimination, and metabolism of fostemsavir (FTR), a prodrug of the HIV-1 attachment inhibitor temsavir (TMR), were investigated in healthy volunteers. FTR was administered with and without ritonavir (RTV), a protease inhibitor previously shown to boost TMR exposures. In vitro studies were also used to identify the enzymes responsible for the metabolism of TMR. Total recovery of the administered dose ranged from 78% to 89%. Approximately 44% to 58% of the dose was excreted in urine, 20%–36% in faeces, and 5% in bile, as TMR and metabolites. RTV had no effect on the recovery of radioactivity in any matrix. Compared to FTR alone, pre-treatment of subjects with RTV increased the exposure of TMR by ∼66% and reduced the exposure of plasma total radioactivity by ∼68%. The major route of TMR elimination was through biotransformation. TMR, M28 (N-dealkylation), and M4 (amide hydrolysis) were the major circulating components in plasma. Pre-treatment with RTV increased the amount of TMR present, decreased the amount of circulating M28, and M4 was unchanged. CYP3A4 metabolism accounted for 21% of the dose, forming multiple oxidative metabolites. This pathway was inhibited by coadministration of RTV.

Fostemsavir is a prodrug of temsavir, a first-in-class attachment inhibitor that binds directly to HIV-1 gp120, preventing initial viral attachment and entry into host CD4 + T cells with demonstrated efficacy in phase 2 and 3. Temsavir is a P-glycoprotein and breast cancer resistance protein (BCRP) substrate; its metabolism is mediated by esterase and CYP3A4 enzymes.

The Lower Mississippi River Alluvial Plain, referred to as the Delta, is an important agricultural region in the southeastern United States. Recent trends in crop type conversion and higher crop yields resulted in increased irrigation demand for surface and groundwater, which can lead to aquifer levels dropping. Estimates of continued increased irrigation adoption are compounded by future climatic estimates suggesting hotter summers with higher unpredictability in precipitation amounts. In these conditions, the long-term sustainability of this system depends on understanding complex surface-groundwater flow interactions at different temporal and spatial scales, and the impacts of agricultural conservation practices on water use. In this study, a description of the development of the integrated AnnAGNPS-MODFLOW technology is provided. The proposed system was evaluated in the Upper Sunflower River watershed, located in the Delta region of Mississippi, to characterize existing conditions through comparison with observed streamflow and well water levels. Additionally, the system was used to evaluate the impact of alternative irrigation and management strategies on water levels in the aquifer at field and watershed scales. The proposed technology provides a management tool critical to understanding and evaluating the impact of agricultural practices, irrigation, and aquifer recharge strategies that are important to sustaining Delta water resources in a changing climate.

Conservation agriculture has proved to be beneficial in terms of securing yield, sustainability of natural resources, and biodiversity of the natural and cultivated ecosystems. The effectiveness of existing and planned conservation practices in targeted watersheds in Tennessee, USA, were evaluated. Two watershed systems were selected in coordination with the U.S. Department of Agriculture - National Resources Conservation Service (NRCS) including four watersheds in Northern Middle Tennessee and six watersheds in West Tennessee.Our objective was accomplished using the Annualized Agricultural Non-Point Source (AnnAGNPS) watershed pollution model to generate watershed simulations for our study areas. The main inputs databases needed include: (1) a 3-m LiDAR based Digital Elevation Model (DEM), (2) weather data from 23 NOAA stations and from AGNPS Climate Generator (agGEM), (3) soil data from the Web Soil Survey (WSS) and complementary soil description of physical and chemical properties from the USDA Soil Data Access website, (4) land use and land cover data describing crop type from 2009 to 2019 from the National Agricultural Statistics Service’s Cropland Data Layer (CDL), and (5) typical farming management practices that were generated by integrating spatiotemporal crop type information at raster grid cell scale (from CDL), average crop yield at county scale (from USDA-NASS), and one-year farming management schedule (from USDA-NRCS). In addition to the AnnAGNPS simulation representing existing conditions, 34 additional AnnAGNPS simulations representing alternative scenarios of conservation practices were evaluated. Eight scenarios depicting the effectiveness of sediment retention ponds under various stream order, stream length, and sediment yield conditions; 4 scenarios were run to depict the effectiveness of crop rotation under various sediment yield-based conditions; 4 scenarios were run to depict the effectiveness of the conservation reserve program (CRP) under various sediment yield-based conditions; and 18 scenarios were run to depict the effectiveness of riparian forest buffer under various buffer width, and sediment yield- based conditions.Preliminary results indicate that the vegetative riparian buffer is a very effective practice that could eliminate up to 80% of the total watershed sediment yield if implemented in every stream of the watershed. Alternatively, creating and maintaining a riparian buffer in just agricultural fields could decrease the sediment yield by 42% to 50% depending on width and by 5 to 6% when implemented in the top sediment producing fields. The projected reduction from sediment retention ponds of sediment yield is 95% in the case of 233 ponds strategically placed across the Western TN watershed system. Crop rotation simulations show that this conservation practice could decrease sediment yield by up to 12% in the extreme scenario of applying it in every soybean agricultural field in the study area, making it less effective than the other simulated conservation practices. CRP decreases the sediment yield by more than 81% percent in the most optimistic scenario and by 10% in the least optimistic scenario.Findings from this study support efforts in guiding future conservation strategies development contributing to water quality and sediment erosion improvement in the state of Tennessee and across the US.

Conservation agencies need information to guide planning activities and allocation of limited mitigation resources at regional scales. Utilization of hydrological modeling tools at sub-watershed scales can adequately represent existing conditions, but information on a few discrete uncoordinated efforts cannot be scaled up to the entire region. Conversely, large scale modeling studies suffer from overgeneralization caused by needed lumping of information. In this study, a multiscale and standardized procedure was sought to characterize water and nonpoint source pollution spatiotemporal dynamics at basin-scale but through detailed field-scale analysis. The AnnAGNPS watershed pollution model was enhanced with new capabilities for simulation of large areas based on an Integrated Technology for Evaluation and Assessment of Multi-scale-hydrological Systems (ITEAMS) approach. Comparisons between the standard and proposed ITEAMS approach indicated no difference in streamflow and small underestimation of suspended sediments during high intensity rainfall events. The ITEAMS approach was applied to a basin with a total area of 3,268,691 ha which was discretized into 469,628 sub-catchments with an average size of 6.8 ha. The resulting 366 linked AnnAGNPS simulations were executed hierarchically generating estimates of water and suspended sediment yield and loads. This pilot study revealed the ITEAMS approach is a viable alternative for modeling and simulating large areas but at high spatiotemporal resolution.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection.METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants.FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005).INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia.FUNDING: UK National Institute for Health Research Health Technology Assessment.