Cellular pharmacology of multi- and duplex drugsconsisting of ethynylcytidine and 5-fluoro-2′-deoxyuridine

Prodrugs can have the advantage over parent drugs in increased activation and cellular uptake. The multidrug ETC-L-FdUrd and the duplex drug ETC-FdUrd are composed of two different monophosphate-nucleosides, 5-fluoro-2′deoxyuridine (FdUrd) and ethynylcytidine (ETC), coupled via a glycerolipid or phosphodiester, respectively. The aim of the study was to determine cytotoxicity levels and mode of drug cleavage. Moreover, we determined whether a liposomal formulation of ETC-L-FdUrd would improve cytotoxic activity and/or cleavage. Drug effects/cleavage were studied with standard radioactivity assays, HPLC and LC-MS/MS in FM3A/0 mammary cancer cells and their FdUrd resistant variants FM3A/TK−. ETC-FdUrd was active (IC50 of 2.2 and 79 nM) in FM3A/0 and TK− cells, respectively. ETC-L-FdUrd was less active (IC50: 7 nM in FM3A/0 vs 4500 nM in FM3A/TK−). Although the liposomal formulation was less active than ETC-L-FdUrd in FM3A/0 cells (IC50:19.3 nM), resistance due to thymidine kinase (TK) deficiency was greatly reduced. The prodrugs inhibited thymidylate synthase (TS) in FM3A/0 cells (80–90%), but to a lower extent in FM3A/TK− (10–50%). FdUMP was hardly detected in FM3A/TK− cells. Inhibition of the transporters and nucleotidases/phosphatases resulted in a reduction of cytotoxicity of ETC-FdUrd, indicating that this drug was cleaved outside the cells to the monophosphates, which was verified by the presence of FdUrd and ETC in the medium. ETC-L-FdUrd and the liposomal formulation were neither affected by transporter nor nucleotidase/phosphatase inhibition, indicating circumvention of active transporters. In vivo, ETC-FdUrd and ETC-L-FdURd were orally active. ETC nucleotides accumulated in both tumor and liver tissues. These formulations seem to be effective when a lipophilic linker is used combined with a liposomal formulation

Data for Surveillance of respiratory viruses among children attending a primary school in rural coastal Kenya

This dataset is acquired from the SPREDstudy which is part of a larger project titled SPReD (Studies of the Pathways of transmission of Respiratory virus Disease) which aims to advance understanding of the nature of spread of respiratory viruses. The study was conducted as a one-year surveillance of respiratory viruses in a rural primary school in Kilifi county, coastal Kenya with the main aim of characterising respiratory virus infection in the school setting and define the role of school-going children in the transmission of these viruses in the general community. The main dataset contains 36 variables and 3384 observations. These data include records of anthropometric measures, acute respiratory infection (ARI) symptoms and laboratory test results from nasal samples obtained from symptomatic school children every week over one school year. Anthropometric measures including the age, grade, weight, height, mid-upper arm circumference, temperature and respiratory rate of each student were recorded every week from a random sample of symptomatic students in each grade. Acute respiratory infection symptoms were also recorded at this time. Nasal samples were screened for 15 virus targets using real-time PCR. Samples were considered positive for a specific target if the ct value was >0 and <=35. The dataset is used to describe the types of respiratory viruses circulating among school-going children