Hydrophilic and lipophilic radiopharmaceuticals as tracers in pharmaceutical development: In vitro – In vivo studies

BACKGROUND: Scintigraphic studies have been performed to assess the release, both in vitro and in vivo, of radiotracers from tablet formulations. Four different tracers with differing physicochemical characteristics have been evaluated to assess their suitability as models for drug delivery. METHODS: In-vitro disintegration and dissolution studies have been performed at pH 1, 4 and 7. In-vivo studies have been performed by scintigraphic imaging in healthy volunteers. Two hydrophilic tracers, ((99m)Tc-DTPA) and ((99m)Tc-MDP), and two lipophilic tracers, ((99m)Tc-ECD) and ((99m)Tc-MIBI), were used as drug models. RESULTS: Dissolution and disintegration profiles, differed depending on the drug model chosen. In vitro dissolution velocity constants indicated a probable retention of the radiotracer in the formulation. In vivo disintegration velocity constants showed important variability for each radiopharmaceutical. Pearson statistical test showed no correlation between in vitro drug release, and in vivo behaviour, for (99m)Tc-DTPA, (99m)Tc-ECD and (99m)Tc-MIBI. High correlation coefficients were found for (99m)Tc-MDP not only for in vitro dissolution and disintegration studies but also for in vivo scintigraphic studies. CONCLUSION: Scintigraphic studies have made a significant contribution to the development of drug delivery systems. It is essential, however, to choose the appropriate radiotracers as models of drug behaviour. This study has demonstrated significant differences in release patterns, depending on the model chosen. It is likely that each formulation would require the development of a specific model, rather than being able to use a generic drug model on the basis of its physicochemical characteristics

A global experiment on motivating social distancing during the COVID-19 pandemic

Significance Communicating in ways that motivate engagement in social distancing remains a critical global public health priority during the COVID-19 pandemic. This study tested motivational qualities of messages about social distancing (those that promoted choice and agency vs. those that were forceful and shaming) in 25,718 people in 89 countries. The autonomy-supportive message decreased feelings of defying social distancing recommendations relative to the controlling message, and the controlling message increased controlled motivation, a less effective form of motivation, relative to no message. Message type did not impact intentions to socially distance, but people’s existing motivations were related to intentions. Findings were generalizable across a geographically diverse sample and may inform public health communication strategies in this and future global health emergencies. Abstract Finding communication strategies that effectively motivate social distancing continues to be a global public health priority during the COVID-19 pandemic. This cross-country, preregistered experiment (n = 25,718 from 89 countries) tested hypotheses concerning generalizable positive and negative outcomes of social distancing messages that promoted personal agency and reflective choices (i.e., an autonomy-supportive message) or were restrictive and shaming (i.e., a controlling message) compared with no message at all. Results partially supported experimental hypotheses in that the controlling message increased controlled motivation (a poorly internalized form of motivation relying on shame, guilt, and fear of social consequences) relative to no message. On the other hand, the autonomy-supportive message lowered feelings of defiance compared with the controlling message, but the controlling message did not differ from receiving no message at all. Unexpectedly, messages did not influence autonomous motivation (a highly internalized form of motivation relying on one’s core values) or behavioral intentions. Results supported hypothesized associations between people’s existing autonomous and controlled motivations and self-reported behavioral intentions to engage in social distancing. Controlled motivation was associated with more defiance and less long-term behavioral intention to engage in social distancing, whereas autonomous motivation was associated with less defiance and more short- and long-term intentions to social distance. Overall, this work highlights the potential harm of using shaming and pressuring language in public health communication, with implications for the current and future global health challenges

The insecticide chlorpyrifos modifies the expression of genes involved in the PXR and AhR pathways in the rainbow trout, Oncorhynchus mykiss

Chlorpyrifos (CPF) is an organophosphate pesticide, commonly detected in water and food. Despite CPF toxicity on aquatic species has been extensively studied, few studies analyze the effects of CPF on fish transcriptional pathways. The Pregnane X receptor (PXR) is a nuclear receptor that is activated by binding to a wide variety of ligands and regulates the transcription of enzymes involved in the metabolism and transport of many endogenous and exogenous compounds. We evaluated the mRNA expression of PXR-regulated-genes (PXR, CYP3A27, CYP2K1, ABCB1, UGT, and ABCC2) in intestine and liver of the rainbow trout, Oncorhynchus mykiss, exposed in vivo to an environmentally relevant CPF concentration. Our results demonstrate that the expression of PXR and PXR-regulated genes is increased in O. mykiss liver and intestine upon exposure to CPF. Additionally, we evaluated the impact of CPF on other cellular pathway involved in xenobiotic metabolism, the Aryl Hydrocarbon Receptor (AhR) pathway, and on the expression and activity of different biotransformation enzymes (CYP2M1, GST, FMO1, or cholinesterases (ChEs)). In contrast to PXR, the expression of AhR, and its target gene CYP1A, are reduced upon CPF exposure. Furthermore, ChE and CYP1A activities are significantly inhibited by CPF, in both the intestine and the liver. CPF activates the PXR pathway in O. mykiss in the intestine and liver, with a more profound effect in the intestine. Likewise, our results support regulatory crosstalk between PXR and AhR pathways, where the induction of PXR coincides with the downregulation of AhR-mediated CYP1A mRNA expression and activity in the intestine