Discriminative Stimulus and Low Abuse Liability Effects of Novel Endomorphin Analogs Suggest a Potential Treatment Indication for Opioid Use Disorder.

Opioid dependence can be difficult to manage using existing pharmacotherapies. A long-acting opioid with low abuse liability that substitutes for a shorter-acting opioid may improve treatment of opioid use disorders (OUDs). We recently characterized an endomorphin (EM) analog (ZH853) that produced a longer duration of antinociception compared with morphine, but did not produce self-administration or several other adverse effects preclinically. Here, we further characterized ZH853 in tests of antinociception, abuse liability, and drug discrimination. A conditioned place preference (CPP) procedure, that included a locomotor activity assessment, was used to test abuse liability in rats. Subsequently, dopamine (DA) cell-somas located in the ventral tegmental area (VTA) from these rats were assessed by size using immunohistochemistry and Stereo Investigator software. A hot-plate antinociception test in male and female mice confirmed central penetration. Morphine-substitution effects of several EM analogs (ZH850, ZH831, and ZH853) were tested in a drug discrimination (DD) procedure in rats. Morphine produced dose-dependent CPP and locomotor sensitization and reduced the size of DA cell somas in VTA, whereas ZH853 did not produce any of these effects relative to control. The antinociceptive effects of ZH853 were µ-receptor selective since ß-funaltrexamine antagonized these effects. Rats responded on a morphine-trained lever when injected with ZH831 and ZH853 during DD experiments. The favorable morphine-substitution effects of these EM analogs relative to their low abuse liability indicate promising novel compounds that may improve treatment of OUD. SIGNIFICANCE STATEMENT: In this experiment, we investigated the preclinical effects of novel endomorphin analogs for use as substitution therapies for opioid use disorder, a problem that has contributed to an opioid overdose epidemic. Several endomorphin analogs substituted for morphine without producing adverse effects, including reward behaviors associated with abuse liability. These compounds have the potential to become important additional tools to treat opioid use disorders.

Management of Localized T1c Prostate Cancer Among Men 75 Years and Older: A National Cancer Database Study.

INTRODUCTION: Elderly men are underrepresented in prostate cancer (PCa) literature, with management based on individualized care pathways and life expectancy. Reports have shown survival benefit with radiation (XRT), surgery, and hormone (ADT) in localized disease. The objective of this study was to assess treatment trends and overall survival (OS) among men 75 years of age and older with cT1c PCa. METHODS: The National Cancer Database was queried to identify patients with cT1c PCa, aged 75 years and older, between 2004 and 2016. We excluded individuals with N1/NX or M1/MX disease, unknown treatment, treatment with both XRT and surgery, surgery other than radical prostatectomy (RP), or PSA > 10 ng/ml. We described 4 treatment cohorts: observation, XRT, surgery, and ADT alone. Treatment trends and OS were analyzed using SPSS. RESULTS: Among 49,843 patients, 7% had surgery, 66% had XRT, 5% had ADT alone, and 22% were observed. From 2004-2016, a large decline in XRT was noted, with an increase in surgery and observation. Men receiving ADT alone were significantly older, with higher Gleason's score, and lower incomes. Cox regression revealed survival benefit for surgery and XRT (HR 0.44 and 0.69, P < .001 respectively); ADT had worse survival than observation (HR 1.23, P < .001). CONCLUSION: Fewer men 75 years of age and older with cT1c PCa are being diagnosed and treated. Rates of XRT have declined, with rises in surgery and observation. Survival benefit was seen for surgery and XRT among elderly men, which highlights the importance of proper patient selection for improved outcomes in a highly individualized sphere.