Design and synthesis of oxytocin glycosides for the treatment of pain and substance use disorder.

Peptide drugs are a promising alternative to classical small molecule therapeutics with diverse applications, ranging from antibiotic resistant infection to prostate cancer. Oxytocin (OT) is a highly evolutionarily conserved peptide neurohormone and has been of interest for pharmaceutical use since 1909. Despite their increased safety profile relative to most small molecule drugs, peptides are poor candidates based on the pharmacokinetic (PK) properties from their peptide nature. Broad application of OT as a drug has been limited by these same PK issues. Several strategies have been proposed to overcome these limitations, among them glycosylation, which was used in combination with other sequence modifications to produce robust antinociception in mouse models, increased selectivity and potency at the OT receptor, and improved stability in rats.

Effects of live-online, group mindfulness training on opioid use and anxiety during buprenorphine treatment: A comparative effectiveness RCT.

BACKGROUND: Office-based opioid treatment with buprenorphine has emerged as a popular evidence-based treatment for opioid use disorder. Unfortunately, psychosocial stress, anxiety, pain, and co-morbid substance use increase patients' risk for relapse. We designed this study to compare the effects of complementing buprenorphine treatment with 24 weeks of a live-online Mindful Recovery Opioid Care Continuum (M-ROCC) group to a time and attention-matched, live-online Recovery Support Group (RSG) active control condition. METHODS: We plan to enroll a maximum of N = 280 and randomize at least N = 192 patients prescribed buprenorphine through referrals from office-based and telemedicine buprenorphine treatment providers and social media advertisements. Participants will be randomly assigned to M-ROCC or RSG and will be blinded to their treatment condition. The primary outcome for this study will be biochemically confirmed periods of abstinence from illicit opioids, as measured by self-reported use and randomly collected, video-observed oral fluid toxicology testing during the final 12 weeks of study participation. Secondary outcomes include changes in Patient-Reported Outcomes Measurement Information System (PROMIS) anxiety and pain interference scores between baseline and week 24. RESULTS: The trial was funded by the National Institutes of Health, HEAL Initiative through NCCIH (R33AT010125). Data collection is projected to end by September 2023, and we expect publication of results in 2024. CONCLUSION: If the M-ROCC intervention is found to be effective in this format, it will demonstrate that live-online mindfulness groups can improve outcomes and address common co-morbidities like anxiety and pain during buprenorphine treatment.

Preference for Male Risk Takers Varies with Relationship Context and Health Status but not COVID Risk.

Risk taking is more commonly shown by males than females and has a signalling function, serving to advertise one's intrinsic quality to prospective mates. Previous research has established that male risk takers are judged as more attractive for short-term flings than long-term relationships, but the environmental and socioeconomic context surrounding female preferences for male risk takers has been overlooked. Using a survey instrument, we examined female preferences for male risk takers across 1304 females from 47 countries. We found preferences for physical risk takers to be more pronounced in females with a bisexual orientation and females who scored high on risk proneness. Self-reported health was positively associated with preferences for high risk takers as short-term mates, but the effect was moderated by country-level health, i.e. the association was stronger in countries with poorer health. The security provided by better health and access to health care may allow females to capitalise on the genetic quality afforded by selecting a risk-prone male whilst concurrently buffering the potential costs associated with the risk taker's lower paternal investment. The risk of contracting COVID-19 did not predict avoidance of risk takers, perhaps because this environmental cue is too novel to have moulded our behavioural preferences. Supplementary Information: The online version contains supplementary material available at 10.1007/s40806-023-00354-3.

Structure-Based Design of Glycosylated Oxytocin Analogues with Improved Selectivity and Antinociceptive Activity.

Acute and chronic pain is often treated with opioids despite the negative side effects of constipation, physical dependence, respiratory depression, and overdose. The misuse of opioid analgesics has given rise to the opioid crisis/epidemic, and alternate nonaddictive analgesics are urgently needed. Oxytocin, a pituitary hormone, is an alternative to the small molecule treatments available and has been used as an analgesic as well as for the treatment and prevention of opioid use disorder (OUD). Clinical implementation is limited by its poor pharmacokinetic profile, a result of the labile disulfide bond between two cysteine residues in the native sequence. Stable brain penetrant oxytocin analogues have been synthesized by replacement of the disulfide bond with a stable lactam and glycosidation of the C-terminus. These analogues show exquisite selectivity for the oxytocin receptor and potent in vivo antinociception in mice following peripheral (i.v.) administration, supporting further study of their clinical potential.

Evaluation of repeated or acute treatment with cannabidiol (CBD), cannabidiolic acid (CBDA) or CBDA methyl ester (HU-580) on nausea and/or vomiting in rats and shrews.

RATIONALE: When acutely administered intraperitoneally, the non-psychoactive cannabinoid cannabidiol (CBD), its acidic precursor cannabidiolic acid (CBDA) and a stable methyl ester of CBDA (HU-580) reduce lithium chloride (LiCl)-induced conditioned gaping in male rats (a selective preclinical model of acute nausea) via activation of the serotonin 1A (5-HT1A) receptor. OBJECTIVES: To utilise these compounds to manage nausea in the clinic, we must determine if their effectiveness is maintained when injected subcutaneously (s.c) and when repeatedly administered. First, we compared the effectiveness of each of these compounds to reduce conditioned gaping following repeated (7-day) and acute (1-day) pretreatments and whether these anti-nausea effects were mediated by the 5-HT1A receptor. Next, we assessed whether the effectiveness of these compounds can be maintained when administered prior to each of 4 conditioning trials (once per week). We also evaluated the ability of repeated CBD (7 days) to reduce LiCl-induced vomiting in Suncus murinus. Finally, we examined whether acute CBD was equally effective in male and female rats. RESULTS: Both acute and repeated (7 day) s.c. administrations of CBD (5 mg/kg), CBDA (1 µg/kg) and HU-580 (1 µg/kg) similarly reduced LiCl-induced conditioned gaping, and these effects were blocked by 5HT1A receptor antagonism. When administered over 4 weekly conditioning trials, the anti-nausea effectiveness of each of these compounds was also maintained. Repeated CBD (5 mg/kg, s.c.) maintained its anti-emetic efficacy in S. murinus. Acute CBD (5 and 20 mg/kg, s.c.) administration reduced LiCl-induced conditioned gaping similarly in male and female rats. CONCLUSION: When administered repeatedly (7 days), CBD, CBDA and HU-580 did not lose efficacy in reducing nausea and continued to act via agonism of the 5-HT1A receptor. When administered across 4 weekly conditioning trials, they maintained their effectiveness in reducing LiCl-induced nausea. Repeated CBD also reduced vomiting in shrews. Finally, CBD's anti-nausea effects were similar in male and female rats. This suggests that these cannabinoids may be useful anti-nausea and anti-emetic treatments for chronic conditions, without the development of tolerance.

Tunable carbocation-based redox active ambiphilic ligands: synthesis, coordination and characterization.

The synthesis of novel redox active ambiphilic ligands L1-L3 and their coordination chemistry to first-row late transition metal halides (M = Co and Ni) is reported. The heterocyclic carbocation scaffolds act as Lewis acid moieties while the pyridine anchor acts as the coordinating Lewis base. The high synthetic tunability of this ligand scaffold allows for control of its rigidity and electronic properties. Anion exchange and coordination of a chloride anion to the metal center was observed resulting in the formation of [MCl3]- metallate. Upon coordination to the pyridine anchor, the metallate centers adopt a canonical tetrahedral geometry, resulting in an overall neutral complex best described as a zwitterionic metallate trichloride bound to a cationic ligand. Characterization techniques including single crystal X-ray diffraction, cyclic voltammetry, and UV-Vis absorption spectroscopy were employed to better understand the structural and chemical properties of the ligands and metal complexes. A possible weak interaction between one of the chlorides and the carbenium moiety in the ligand is observed in crystals of both of the Co(ii) and Ni(ii) complexes with ligand L1. Density functional theory (DFT) calculations support that this electrostatic interaction for complexes 2a and 2b exists only in the solid state.

Molecular Orbital Insights of Transition Metal-Stabilized Carbocations.

Transition metal-stabilized carbocations are characterized by synthetically valuable interactions, yet, to date there are no comprehensive reports of the many bonding modes that can exist between a metal and carbocation. This review summarizes developments in these complexes to provide a clear picture of their properties and reactivities. In order to strategically exploit them, we propose this summary of the different bonding modes for transition metal-carbocation complexes. These models will help chemists understand the orbital interactions involved in these compounds so that they can approach their synthetic goals most effectively. Multiple transition metals and carbocations will be discussed.

Waiting for surgery after orthopaedic trauma.

Nursing staff on a paediatric surgical ward were concerned about delays experienced by children waiting to go to theatre following orthopaedic trauma, and their families. A facilitated action research approach was used which involved describing the issue, gathering information from a range of sources and introducing changes to the process of care. A flowchart was developed to clarify the stages and the staff involved in admitting a child with orthopaedic trauma for surgery. A white board was introduced to record information on 'trauma' patients. A facilitated action research process offers a flexible and accessible way for staff to develop a range of transferable research and change management skills.