Encapsulation of Small Gas Molecules by Cryptophane-111 in Organic Solution. 1. Size- and Shape-Selective Complexation of Simple Hydrocarbons

International audienceThe reversible trapping of small hydrocarbons and other gases by cryptophane-111 (1) in organic solution was characterized with variable-temperature 1H NMR spectroscopy. Characteristic spectral changes observed upon guest binding allowed kinetic and thermodynamic data to be readily extracted, permitting quantification and comparison of different host−guest interactions. Previous work (J. Am. Chem. Soc. 2007, 129, 10332) demonstrated that 1, the smallest cryptophane to date, forms a complex with xenon with remarkably high affinity. Presently, it is shown that 1 also exhibits slow exchange dynamics with methane at reduced temperatures (δbound = −5.2 ppm) with an association constant Ka = 148 M−1 at 298 K. In contrast, ethane and ethylene are poorly recognized by 1 with Ka values of only 2 M−1 and 22 M−1, respectively; moreover, chloromethane (whose molecular volume is similar to that of xenon, ∼42 Å3) is not observed to bind to 1. Separately, molecular hydrogen (H2) gas is observed to bind 1, but in contrast to other ligands presently studied, H2 complexation is spectrally manifested by fast exchange throughout virtually the entire range of available conditions, as well as by a complex dependence of the guest 1H resonance frequency upon temperature and host concentration. Taken together, these results establish 1 as a selective host for small gases, with implications for the design of size- and geometry-selective sensors targeted for various gas molecules

pH-Sensitive MR Responses Induced by Dendron-Functionalized SPIONs

We report a series of investigations of the pH-sensitive magnetic resonance (MR) responses of various surface-functionalized SPIONs (superparamagnetic iron oxide nanoparticles). First, functionalization of ~12 nm highly monocrystalline SPION cores with three different generations of melamine-dendrons was optimized to give agents with high molar relaxivities (e.g. ~300 mM·s at 7 T and ~20-30 mM·s at 0.5 T) and excellent aqueous stabilities. Molar relaxivities were found to exhibit great sensitivity to pH at physiologically-relevant ionic strengths, with sharp inflections observed at pH values near the p of the melamine monomer. The strength of the effect was observed to grow with increasing dendron generation (with concomitant shift in the position of the main pH inflection). Opposing behavior in and * trends may be exploited to provide a ratiometric MR response to pH. Combined with TEM and corresponding MR measurements from solutions of varying ionic strengths, these results are consistent with the pH-sensitive behavior originating from transient, reversible SPION clustering modulated by an interplay between SPION surface charge density and solution ionic strength. Studies of SPION cellular uptake and MR response in HeLa cell cultures are also presented. Finally, comparisons with the MR responses of SPIONs with alternative functionalities-derivatives of nitrilotriacetic acid or poly(1-vinylimidazole)-indicate that these types of pH-sensitive MR responses can be highly dependent upon the chemical composition of the surface species (and thus amenable to modulation through rational design)

pH-Sensitive MR Responses Induced by Dendron-Functionalized SPIONs

We report a series of investigations of the pH-sensitive magnetic resonance (MR) responses of various surface-functionalized SPIONs (superparamagnetic iron oxide nanoparticles). First, functionalization of ∼12 nm highly monocrystalline SPION cores with three different generations of melamine dendrons was optimized to give agents with high molar relaxivities (e.g., <i>R</i>₂^<i>m</i> ∼300 mM^–1·s^–1 at 7 T and <i>R</i>₁^<i>m</i> ∼20–30 mM^–1·s^–1 at 0.5 T) and excellent aqueous stabilities. Molar relaxivities were found to exhibit great sensitivity to pH at physiologically relevant ionic strengths, with sharp inflections observed at pH values near the p<i>K</i>_a of the melamine monomer. The strength of the effect was observed to grow with increasing dendron generation (with a concomitant shift in the position of the main pH inflection). Opposing behavior in <i>R</i>₂^<i>m</i> and <i>R</i>₂*^<i>m</i> trends may be exploited to provide a ratiometric MR response to pH. Combined with TEM and corresponding MR measurements from solutions of varying ionic strengths, these results are consistent with the pH-sensitive behavior originating from transient, reversible SPION clustering modulated by an interplay between SPION surface charge density and solution ionic strength. Studies of SPION cellular uptake and MR response in HeLa cell cultures are also presented. Finally, comparisons with the MR responses of SPIONs with alternative functionalitiesderivatives of nitrilotriacetic acid or poly­(1-vinylimidazole)indicate that these types of pH-sensitive MR responses can be highly dependent upon the chemical composition of the surface species (and thus amenable to modulation through rational design)

Recommendations for selecting drug–drug interactions for clinical decision support

PURPOSE: To recommend principles for including drug-drug interactions (DDIs) in clinical decision support. METHODS: A conference series was conducted to improve clinical decision support (CDS) for DDIs. The Content Workgroup met monthly by webinar from January 2013 to February 2014, with two in-person meetings to reach consensus. The workgroup consisted of 20 experts in pharmacology, drug information, and CDS from academia, government agencies, health information (IT) vendors, and healthcare organizations. Workgroup members addressed four key questions: (1) What process should be used to develop and maintain a standard set of DDIs?; (2) What information should be included in a knowledgebase of standard DDIs?; (3) Can/should a list of contraindicated drug pairs be established?; and (4) How can DDI alerts be more intelligently filtered? RESULTS: To develop and maintain a standard set of DDIs for CDS in the United States, we recommend a transparent, systematic, and evidence-driven process with graded recommendations by a consensus panel of experts and oversight by a national organization. We outline key DDI information needed to help guide clinician decision-making. We recommend judicious classification of DDIs as contraindicated, as only a small set of drug combinations are truly contraindicated. Finally, we recommend more research to identify methods to safely reduce repetitive and less relevant alerts. CONCLUSION: A systematic ongoing process is necessary to select DDIs for alerting clinicians. We anticipate that our recommendations can lead to consistent and clinically relevant content for interruptive DDIs, and thus reduce alert fatigue and improve patient safety