Advanced Prodrug Strategies in Nucleoside and Non-Nucleoside Antiviral Agents: A Review of the Recent Five Years

Background: Poor pharmacokinetic profiles and resistance are the main two drawbacks from which currently used antiviral agents suffer, thus make them excellent targets for research, especially in the presence of viral pandemics such as HIV and hepatitis C. Methods: The strategies employed in the studies covered in this review were sorted by the type of drug synthesized into ester prodrugs, targeted delivery prodrugs, macromolecular prodrugs, other nucleoside conjugates, and non-nucleoside drugs. Results: Utilizing the ester prodrug approach a novel isopropyl ester prodrug was found to be potent HIV integrase inhibitor. Further, employing the targeted delivery prodrug zanamivir and valine ester prodrug was made and shown a sole delivery of zanamivir. Additionally, VivaGel, a dendrimer macromolecular prodrug, was found to be very efficient and is now undergoing clinical trials. Conclusions: Of all the strategies employed (ester, targeted delivery, macromolecular, protides and nucleoside analogues, and non-nucleoside analogues prodrugs), the most promising are nucleoside analogues and macromolecular prodrugs. The macromolecular prodrug VivaGel works by two mechanisms: envelope mediated and receptor mediated disruption. Nucleotide analogues have witnessed productive era in the recent past few years. The era of non-interferon based treatment of hepatitis (through direct inhibitors of NS5A) has dawned

PREDICTING THE SUMMER TEMPERATURE OF SMALL STREAMS IN SOUTHWESTERN WISCONSIN 1

One of the biggest challenges in managing cold water streams in the Midwest is understanding how stream temperature is controlled by the complex interactions among meteorologic processes, channel geometry, and ground water inflow. Inflow of cold ground water, shade provided by riparian vegetation, and channel width are the most important factors controlling summer stream temperatures. A simple screening model was used to quantitatively evaluate the importance of these factors and guide management decisions. The model uses an analytical solution to the heat transport equation to predict steady-state temperature throughout a stream reach. The model matches field data from four streams in southwestern Wisconsin quite well (typically within 1°C) and helps explain the observed warming and cooling trends along each stream reach. The distribution of ground water inflow throughout a stream reach has an important influence on stream temperature, and springs are especially effective at providing thermal refuge for fish. Although simple, this model provides insight into the importance of ground water and the impact different management strategies, such as planting trees to increase shade, may have on summer stream temperature.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74032/1/j.1752-1688.2005.tb03714.x.pd

Long-term trends in river flow: a case study of the Soła River (Polish Carpathians)

This study analyses potential trends in river flow for the most recent 60 years (1956– 2015). The study area is situated in the Soła catchment in the Polish Carpathians. The focus of the study was to evaluate long-term trends in mean monthly river flow for each season of the year as well as to compare the direction of these trends for sites located a distance upstream and downstream from a cascade of three dams built on the Soła River. Moreover, potential long-term trends in seasonal precipitation were also studied. The data indicate a significant increase in minimum discharge during the winter for the upstream site. Increases in mean and maximum discharge are significant for spring at that site as well. In contrast, a significant decrease in minimum discharge was identified for the downstream site during the spring. Moreover, significant decreases in mean and minimum discharge were noted for the summer season at the downstream site only. No trends in discharge were identified for the autumn at either site. Significant trends in precipitation were noted for each season of the year, with increases during the winter, spring, and autumn (3.6–9.8 mm per decade) in the vicinity of the upstream site, but a decrease in minimum summer precipitation (–5.0 mm per decade) at the downstream site. The revealed differences in the direction of seasonal trends for the upstream and downstream sites studied suggest an anthropogenic impact on river flow downstream from the cascade of dams. Overall, the identified decrease in summer discharge at the downstream site, accompanied by a decrease in summer precipitation, indicate the need for adaptive water management in the studied catchment to ensure water availability for the summer season

Simulating effects of hydro-dam alteration on thermal regime and wild steelhead recruitment in a stable-flow Lake Michigan tributary

Hydroelectric dams may affect anadromous fish survival and recruitment by limiting access to upstream habitats and adversely affecting quality of downstream habitats. In the Manistee River, a tributary to Lake Michigan, two hydroelectric dams potentially limit recruitment of anadromous rainbow trout (steelhead) by increasing tailrace water temperatures to levels that significantly reduce survival of young-of-year (YOY) fish. The objectives of this study were to determine whether proposed restoration scenarios (dam removals or a bottom withdrawal retrofit) would alter the Manistee River thermal regime and, consequently, improve wild steelhead survival and recruitment. Physical process models were used to predict Manistee River thermal regimes following each dam alteration scenario. Empirical relationships were derived from historical field surveys to quantify the effect of temperature on YOY production and potential recruitment of Manistee River steelhead. Both dam alteration scenarios lowered summer temperatures and increased steelhead recruitment by between 59% and 129%, but total recruitments were still low compared to other Great Lakes tributaries. Considering only temperature effects, bottom withdrawal provides the greatest promise for increasing natural steelhead recruitment by decreasing the likelihood of year-class failures in the warmest summers. Results of this study may allow managers to evaluate mitigation alternatives for Manistee River dams during future relicensing negotiations, and illustrate the utility of physical process temperature models in groundwater-fed rivers. Copyright © 2004 John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/35294/1/746_ftp.pd

Advanced Prodrug Strategies in Nucleoside and Non-Nucleoside Antiviral Agents: A Review of the Recent Five Years

Background: Poor pharmacokinetic profiles and resistance are the main two drawbacks from which currently used antiviral agents suffer, thus make them excellent targets for research, especially in the presence of viral pandemics such as HIV and hepatitis C. Methods: The strategies employed in the studies covered in this review were sorted by the type of drug synthesized into ester prodrugs, targeted delivery prodrugs, macromolecular prodrugs, other nucleoside conjugates, and non-nucleoside drugs. Results: Utilizing the ester prodrug approach a novel isopropyl ester prodrug was found to be potent HIV integrase inhibitor. Further, employing the targeted delivery prodrug zanamivir and valine ester prodrug was made and shown a sole delivery of zanamivir. Additionally, VivaGel, a dendrimer macromolecular prodrug, was found to be very efficient and is now undergoing clinical trials. Conclusions: Of all the strategies employed (ester, targeted delivery, macromolecular, protides and nucleoside analogues, and non-nucleoside analogues prodrugs), the most promising are nucleoside analogues and macromolecular prodrugs. The macromolecular prodrug VivaGel works by two mechanisms: envelope mediated and receptor mediated disruption. Nucleotide analogues have witnessed productive era in the recent past few years. The era of non-interferon based treatment of hepatitis (through direct inhibitors of NS5A) has dawned

A new method for nonlinear dynamic modeling of wheel/rail multiple contacts.

A new method for nonlinear dynamic modeling of wheel/rail multiple contacts

Advanced Prodrug Strategies in Nucleoside and Non-Nucleoside Antiviral Agents: A Review of the Recent Five Years

Background: Poor pharmacokinetic profiles and resistance are the main two drawbacks from which currently used antiviral agents suffer, thus make them excellent targets for research, especially in the presence of viral pandemics such as HIV and hepatitis C. Methods: The strategies employed in the studies covered in this review were sorted by the type of drug synthesized into ester prodrugs, targeted delivery prodrugs, macromolecular prodrugs, other nucleoside conjugates, and non-nucleoside drugs. Results: Utilizing the ester prodrug approach a novel isopropyl ester prodrug was found to be potent HIV integrase inhibitor. Further, employing the targeted delivery prodrug zanamivir and valine ester prodrug was made and shown a sole delivery of zanamivir. Additionally, VivaGel, a dendrimer macromolecular prodrug, was found to be very efficient and is now undergoing clinical trials. Conclusions: Of all the strategies employed (ester, targeted delivery, macromolecular, protides and nucleoside analogues, and non-nucleoside analogues prodrugs), the most promising are nucleoside analogues and macromolecular prodrugs. The macromolecular prodrug VivaGel works by two mechanisms: envelope mediated and receptor mediated disruption. Nucleotide analogues have witnessed productive era in the recent past few years. The era of non-interferon based treatment of hepatitis (through direct inhibitors of NS5A) has dawned