Obligations of Contracts: Intent and Distortion

<p><b>Introduction:</b> Treosulfan is an alkylating agent that is used for the treatment of ovarian cancer and for conditioning prior to stem cell transplantation. It is a prodrug that is activated non-enzymatically to two active epoxides.</p> <p><b>Objectives:</b> To optimize a protocol for both <i>in vivo</i> samples handling and <i>in vitro</i> drug preparation. Treosulfan stability was tested in biological fluids at different conditions as well as for its cytotoxicity on cell lines.</p> <p><b>Results:</b> Plasma samples can be safely frozen for a short period up to 8 h, however; for longer periods, samples should be acidified. Urine samples and cell culture media can be safely frozen regardless their pH. For <i>in vitro</i> investigations, incubation of treosulfan at 37 °C for 24 h activated 100% of the drug. Whole blood acidification should be avoided for the risk of hemolysis. Finally; treosulfan cytotoxicity on HL-60 cells has increased following pre-incubation for 24 h at 37 °C compared to K562 cell line.</p> <p><b>Conclusion:</b> The stability profiling of treosulfan provided a valuable reference for handling of biological samples for both <i>in vivo</i> and <i>in vitro</i> studies. These results can be utilized for further investigations concerning the drug kinetics and dynamics in addition to the development of new pharmaceutical formulations.</p

3‑Oxoisoindoline-1-carboxamides: Potent, State-Dependent Blockers of Voltage-Gated Sodium Channel Na_V1.7 with Efficacy in Rat Pain Models

The voltage-gated sodium channel Na_V1.7 is believed to be a critical mediator of pain sensation based on clinical genetic studies and pharmacological results. Clinical utility of nonselective sodium channel blockers is limited due to serious adverse drug effects. Here, we present the optimization, structure–activity relationships, and in vitro and in vivo characterization of a novel series of Na_V1.7 inhibitors based on the oxoisoindoline core. Extensive studies with focus on optimization of Na_V1.7 potency, selectivity over Na_V1.5, and metabolic stability properties produced several interesting oxoisoindoline carboxamides (<b>16A</b>, <b>26B</b>, <b>28</b>, <b>51</b>, <b>60</b>, and <b>62</b>) that were further characterized. The oxoisoindoline carboxamides interacted with the local anesthetics binding site. In spite of this, several compounds showed functional selectivity versus Na_V1.5 of more than 100-fold. This appeared to be a combination of subtype and state-dependent selectivity. Compound <b>28</b> showed concentration-dependent inhibition of nerve injury-induced ectopic in an ex vivo DRG preparation from SNL rats. Compounds <b>16A</b> and <b>26B</b> demonstrated concentration-dependent efficacy in preclinical behavioral pain models. The oxoisoindoline carboxamides series described here may be valuable for further investigations for pain therapeutics