Interdomain Twists of Human Thymidine Phosphorylase and its Active-Inactive Conformations: Binding of 5-FU and its Analogues to hTP vs. DPD

5‐fluorouracil (5‐FU) is an anticancer drug, which inhibits human thymidine phosphorylase (hTP) and plays a key role in maintaining the process of DNA replication and repair. It is involved in regulating pyrimidine nucleotide production, by which it inhibits the mechanism of cell proliferation and cancerous tumor growth. However, up to 80% of the administered drug is metabolized by dihydropyrimidine dehydrogenase (DPD). This work compares binding of 5‐FU and its analogues to hTP and DPD, and suggests strategies to reduce drug binding to DPD to decrease the required dose of 5‐FU. An important feature between the proteins studied here was the difference of charge distribution in their binding sites, which can be exploited for designing drugs to selectively bind to the hTP. The 5‐FU presence was thought to be required for a closed conformation. Comparison of the calculation results pertaining to unliganded and liganded protein showed that hTP could still undergo open–closed conformations in the absence of the ligand; however, the presence of a positively charged ligand better stabilizes the closed conformation and rigidifies the core region of the protein more than unliganded or neutral liganded system. The study has also shown that one of the three hinge segments linking the two major α and α/β domains of the hTP is an important contributing factor to the enzyme's open–close conformational twist during its inactivation–activation process. In addition, the angle between the α/β‐domain and the α‐domain has shown to undergo wide rotations over the course of MD simulation in the absence of a phosphate, suggesting that it contributes to the stabilization of the closed conformation of the hTP

Opioid and Sedative Coprescription: Prescribing Patterns after an ICU Admission

Background: Opioid misuse constitutes a health care crisis in Canada, and coprescription of opioids with sedatives has been associated with adverse events. Opioids and sedatives are frequently administered in the intensive care unit (ICU). The rate of continuation of opioid–sedative combinations after an ICU admission at the study institution was unknown. Objectives: To determine the rates of opioid and sedative coprescriptions following an ICU admission and to identify factors associated with continuation of hospital-initiated opioid–sedative coprescriptions at ICU transfer and hospital discharge. Methods: This retrospective chart review involved patients admitted to ICUs at a tertiary care centre between April 1, 2018, and March 31, 2019. Baseline characteristics were obtained from a clinical database and medication information from medication reconciliation forms. An opioid coprescription was defined as prescription of an opioid in combination with a sedative (benzodiazepine, z-drug, gabapentinoid, tricyclic antidepressant, or antipsychotic), and hospital-initiated coprescriptions encompassed various predefined scenarios of therapy started or modified before ICU transfer. Factors associated with hospital-initiated opioid coprescription were analyzed by multivariable logistic regression. Results: A total of 735 patients met the inclusion criteria. At ICU transfer, 23.0% (169/735) of the patients had an opioid coprescription, and 87.0% (147/169) of these coprescriptions were hospital-initiated. At hospital discharge, 8.6% (44/514) of the patients had an opioid coprescription, and 56.8% (25/44) of these coprescriptions were hospital-initiated. Male sex, home opioid coprescription, surgical patient, prolonged hospital stay, and in-hospital death were significantly associated with hospital-initiated opioid coprescription at the time of ICU transfer. Home opioid coprescription was significantly associated with opioid coprescription at the time of hospital discharge. Conclusions: Hospital-initiated opioid coprescriptions accounted for the majority of opioid coprescriptions at ICU transfer and hospital discharge. Pharmacists should assess all opioid coprescriptions to determine whether discontinuation and/or dose reduction is appropriate. RÉSUMÉ Contexte : L’abus d’opioïdes est une crise sanitaire au Canada, et les opioïdes coprescrits avec des sédatifs ont été associés à des événements indésirables. Les opioïdes et les sédatifs sont fréquemment utilisés en unité de soins intensifs (USI). Sur le lieu de l’étude, on ne connaissait pas le taux de maintien de l’utilisation de la combinaison opioïdes-sédatifs après une admission en USI. Objectifs : Déterminer les taux de coprescription d’opioïdes et de sédatifs suite à une admission en USI et identifier les facteurs associés au maintien de l’utilisation des coprescriptions d’opioïdes et de sédatifs amorcées par l’hôpital au moment du transfert hors de l’USI et du congé hospitalier. Méthodes : Cet examen rétrospectif des dossiers portait sur des patients admis en USI d’un centre de soins tertiaires entre le 1er avril 2018 et le 31 mars 2019. Les caractéristiques de base ont été obtenues à partir d’une base de données clinique et des informations sur les médicaments à partir des formulaires de bilan comparatif des médicaments. Une coprescription d’opioïdes a été définie comme « La prescription d’un opioïde associée à un sédatif (benzodiazépine, médicament z, gabapentinoïde, antidépresseur tricyclique ou antipsychotique) ». Les « coprescriptions amorcées par l’hôpital » correspondaient à des coprescriptions initiées ou modifiées avant le transfert hors de l’USI, selon des scénarios préalablement définis. Les facteurs associés à la coprescription d’opioïdes amorcée par l’hôpital ont été analysés par régression logistique multivariée. Résultats : Au total, 735 patients répondaient aux critères d’inclusion. Lors du transfert hors de l’USI, des opioïdes étaient coprescrits à 23,0 % (169/735) d’entre eux; de ces coprescriptions, 87,0 % (147/169) étaient amorcées par l’hôpital. Au moment du congé hospitalier, des opioïdes étaient coprescrits à 8,6 % (44/514) d’entre eux; de ces coprescriptions, 56,8 % (25/44) étaient amorcées par l’hôpital. Le sexe masculin, la coprescription d’opioïdes à domicile, l’admission en chirurgie, le séjour prolongé à l’hôpital et le décès à l’hôpital étaient fortement associés à la coprescription d’opioïdes amorcée par l’hôpital au moment du transfert hors de l’USI. La coprescription d’opioïdes à domicile était fortement associée à la coprescription d’opioïdes au moment du congé de l’hôpital. Conclusions : Les coprescriptions d’opioïdes amorcées par l’hôpital représentaient la majorité des coprescriptions au moment du transfert hors de l’USI et au moment du congé de l’hôpital. Les pharmaciens doivent évaluer toutes les coprescriptions d’opioïdes pour déterminer si l’arrêt et/ou la réduction de la dose est appropriée

Molecular Dynamics Studies for Optimization of Noncovalent Loading of Vinblastine on Single-Walled Carbon Nanotube

Carbon nanotubes (CNTs) have become one of the most promising candidates for transporting drugs to target sites because of their size scale, huge surface area, and high cellular uptake. Many experimental studies of carbon nanotube drug delivery have been performed in the past decade. However, interactions with one of the essential antimitotic agentsvinblastineand carbon nanotubes have yet to be investigated. Here we present computational studies of the interactions between vinblastine and carbon nanotubes under different conditions. We studied vinblastine–carbon nanotube interactions with one to three vinblastine molecules loaded, with armchair, chiral, and zigzag tube structures, with nonfunctionalized and ester-functionalized carbon nanotubes at 277 and 300 K. Terminal esterification of carbon nanotubes strengthened the drug–carrier interactions of all systems at 300 K. The functionalized carbon nanotubes of armchair type were suitable for drug delivery at both 277 and 300 K due to the strong drug–carrier interactions. The functionalized chiral nanotubes have been shown to be especially effective for the drug transportation at 277 K due to the enhanced drug–carrier interactions at the low temperature

Polarizable Force Field with a σ‑Hole for Liquid and Aqueous Bromomethane

Bromomethane (CH₃Br) is an acutely toxic environmental pollutant that contributes to ozone depletion. Molecular simulation could be a valuable tool for studying its partitioning and transport in the environment if an accurate molecular model was available. The generalized Amber force field (GAFF), OPLS (optimized potentials for liquid simulations) force field, and CHARMM general force field (CGenFF) were tested for their ability to model the physical properties of liquid bromomethane. The OPLS force field was in fairly good agreement with experiment, while CGenFF and GAFF were significantly in error. The Br Lennard-Jones parameters of the GAFF and CGenFF models were reparameterized, but their radial distribution functions still have significant deviations from those calculated by ab initio molecular dynamics (AIMD). A Drude polarizable force field for bromomethane was parametrized with an off-center positively charged site to represent the C–Br σ-hole. This model is in good agreement with the bulk physical properties and the AIMD RDFs. The modest solubility of bromomethane was reproduced by this model, with dispersion interactions being the dominant water–solute interaction. The water–solute electrostatic interactions are a smaller factor in solubility. This model predicts bromomethane to have a 13 kJ mol^–1 surface excess potential at the water–vapor interface

Looking Beyond Income and Education

IntroductionHealthcare spending occurs disproportionately among a very small portion of the population. Research on these high-cost users (HCUs) of health care has been overwhelmingly cross-sectional in nature and limited to the few sociodemographic and clinical characteristics available in health administrative databases. This study is the first to bridge this knowledge gap by applying a population health lens to HCUs. We investigate associations between a broad range of SES characteristics and future HCUs.MethodsA cohort of adults from two cycles of large, nationally representative health surveys conducted in 2003 and 2005 was linked to population-based health administrative databases from a universal healthcare plan for Ontario, Canada. Comprehensive person-centered estimates of annual healthcare spending were calculated for the subsequent 5 years following interview. Baseline HCUs (top 5%) were excluded and healthcare spending for non-HCUs was analyzed. Adjusted for predisposition and need factors, the odds of future HCU status (over 5 years) were estimated according to various individual, household, and neighborhood SES factors. Analyses were conducted in 2014.ResultsLow income (personal and household); less than post-secondary education; and living in high-dependency neighborhoods greatly increased the odds of future HCUs. After adjustment, future HCU status was most strongly associated with food insecurity, personal income, and non-homeownership. Living in highly deprived or low ethnic concentration neighborhoods also increased the odds of becoming an HCU.ConclusionsFindings suggest that addressing social determinants of health, such as food and housing security, may be important components of interventions aiming to improve health outcomes and reduce costs