The Buprenorphine Analogue BU10119 Attenuates Drug-Primed and Stress-Induced Cocaine Reinstatement in Mice.

There are no Food and Drug Administration-approved medications for cocaine use disorder, including relapse. The µ-opioid receptor (MOPr) partial agonist buprenorphine alone or in combination with naltrexone has been shown to reduce cocaine-positive urine tests and cocaine seeking in rodents. However, there are concerns over the abuse liability of buprenorphine. Buprenorphine's partial agonist and antagonist activity at the nociception receptor (NOPr) and κ-opioid receptor (KOPr), respectively, may contribute to its ability to inhibit cocaine seeking. Thus, we hypothesized that a buprenorphine derivative that exhibits antagonist activity at MOPr and KOPr with enhanced agonist activity at the NOPr could provide a more effective treatment. Here we compare the pharmacology of buprenorphine and two analogs, BU10119 and BU12004, in assays for antinociception and for cocaine- and stress-primed reinstatement in the conditioned place preference paradigm. In vitro and in vivo assays showed that BU10119 acts as an antagonist at MOPr, KOPr, and δ-opioid receptor (DOPr) and a partial agonist at NOPr, whereas BU12004 showed MOPr partial agonist activity and DOPr, KOPr, and NOPr antagonism. BU10119 and buprenorphine but not BU12004 lessened cocaine-primed reinstatement. In contrast, BU10119, BU12004, and buprenorphine blocked stress-primed reinstatement. The selective NOPr agonist SCH221510 but not naloxone decreased cocaine-primed reinstatement. Together, these findings are consistent with the concept that NOPr agonism contributes to the ability of BU10119 and buprenorphine to attenuate reinstatement of cocaine-conditioned place preference in mice. The findings support the development of buprenorphine analogs lacking MOPr agonism with increased NOPr agonism for relapse prevention to cocaine addiction. SIGNIFICANCE STATEMENT: There are no Food and Drug Administration-approved medications for cocaine use disorder. Buprenorphine has shown promise as a treatment for cocaine relapse prevention; however, there are concerns over the abuse liability of buprenorphine. Here we show a buprenorphine analogue, BU10119, which lacks µ-opioid receptor agonism and inhibits cocaine-primed and stress-primed reinstatement in a conditioned place-preference paradigm. The results suggest the development of BU10119 for the management of relapse to cocaine seeking.

Aromatic-Amine Pendants Produce Highly Potent and Efficacious Mixed Efficacy µ-Opioid Receptor (MOR)/δ-Opioid Receptor (DOR) Peptidomimetics with Enhanced Metabolic Stability.

We previously reported a novel SAR campaign that converted a metabolically unstable series of µ-opioid receptor (MOR) agonist/δ-opioid receptor (DOR) antagonist bicyclic core peptidomimetics with promising analgesic activity and reduced abuse liabilities into a more stable series of benzylic core analogues. Herein, we expanded the SAR of that campaign and determined that the incorporation of amines into the benzylic pendant produces enhanced MOR-efficacy in this series, whereas the reincorporation of an aromatic ring into the pendant enhanced MOR-potency. Two compounds, which contain a piperidine (14) or an isoindoline (17) pendant, retained the desired opioid profile in vitro, possessed metabolic half-lives of greater than 1 h in mouse liver microsomes (MLMs), and were active antinociceptive agents in the acetic acid stretch assay (AASA) at subcutaneous doses of 1 mg/kg.

Have you "CORED" lately? A comprehensive operating room evacuation drill.

INTRODUCTION: Crises in the operating room (OR) are uncommon events that require an expeditious response from all providers to minimize morbidity and mortality to both patients and staff. Evacuation during a surgical procedure presents a unique challenge. There is a paucity of data on the ideal response, ideal times, and training needs for hospital staff. METHODS: The authors herein describe a full-scale simulation exercise of the emergent mid-procedure evacuation of seven ORs. RESULTS: Median time to evacuate from the OR and reach the Post-Anesthesia Care Unit safety point was 3:50 minutes (range, 1:22 minutes to 6:00 minutes). Multiple lessons were learned from direct observation, post-drill debrief, and post-drill survey of participants. CONCLUSIONS: Emergent mid-procedure evacuation of ORs can be expeditious if needed. Critical themes in leadership, communication, and coordination of care were discovered. Surgeons, anesthesiologists, and OR staff should consider performing an OR evacuation drill to improve their local efficacy and efficiency in emergent OR evacuation.

A comparison of command center activations versus disaster drills at three institutions from 2013 to 2015.

OBJECTIVE: Disaster exercises often simulate rare, worst-case scenario events that range from mass casualty incidents to severe weather events. In actuality, situations such as information system downtimes and physical plant failures may affect hospital continuity of operations far more significantly. The objective of this study is to evaluate disaster drills at two academic and one community hospital to compare the frequency of planned drills versus real-world events that led to emergency management command center activation. DESIGN: Emergency management exercise and command center activation data from January 1, 2013 to October 1, 2015 were collected from a database. The activations and drills were categorized according to the nature of the event. Frequency of each type of event was compared to determine if the drills were representative of actual activations. RESULTS: From 2013 to 2015, there were a total of 136 command center activations and 126 drills at the three hospital sites. The most common reasons for command center activations included severe weather (25 percent, n = 34), maintenance failure (19.9 percent, n = 27), and planned mass gathering events (16.9 percent, n = 23). The most frequent drills were process tests (32.5 percent, n = 41), hazardous material-related events (22.2 percent, n = 28), and in-house fires (15.10 percent, n = 19). CONCLUSION: Further study of the reasons behind why hospitals activate emergency management plans may inform better preparedness drills. There is no clear methodology used among all hospitals to create drills and their descriptions are often vague. There is an opportunity to better design drills to address specific purposes and events.

Channel blocking of MspA revisited.

Porin A from Mycobacterium smegmatis (MspA) is a highly stable, octameric channel protein, which acts as the main transporter of electrolytes across the cell membrane. MspA features a narrow, negatively charged constriction zone, allowing stable binding of various analytes thereby blocking the channel. Investigation of channel blocking of mycobacterial porins is of significance in developing alternate treatment methods for tuberculosis. The concept that ruthenium(II)quaterpyridinium complexes have the capability to act as efficient channel blockers for MspA and related porins, emerged after very high binding constants were measured by high-performance liquid chromatography and steady-state luminescence studies. Consequently, the interactions between the ruthenium(II) complex RuC2 molecules and MspA, leading to RuC2@MspA assemblies, have been studied utilizing time-resolved absorption/emission, atomic force microscopy, dynamic light scattering, ζ potential measurements, and isothermal titration calorimetry. The results obtained provide evidence for the formation of clusters/large aggregates of RuC2 and MspA. The results are of interest with respect to utilizing prospective channel blockers in porins. The combination of results from conceptually different techniques shed some light onto the chemical nature of MspA-channel blocker interactions thus contributing to the development of a paradigm for channel blocking.