Comparison of the Behavioral Pharmacology of Phencyclidine to Related Compounds

Phencyclidine (PCP) belongs to a class of drugs with a unique and characteristic spectra of pharmacological activity. PCP has recently become a major drug of abuse. Structural analogues of PCP have also been reported in street use. The following experiments explore the behavioral pharmacology of PCP and several compounds with PCP-like activity. In Experiment I the effects of PCP were compared to three structural analogues in rhesus monkeys trained to lever press on a fixed-interval 5 min schedule of food presentation. Dose-response curves and potency estimates were determined for PCP, N-ethyl-1-phenylcyclohexylamine (PCE), 1-(1-(2-thienyl) cyclohexyl) piperidine (TCP) and ketamine.The effects of all four drugs on response rates were dependent on the baseline rate of responding. High doses of all four drugs decreased overall response rates. Onset and duration of drug effects were also determined and compared. In Experiments II through VI the drug discrimination paradigm was used. Animals were trained to discriminate PCP (rats, 3.0 mg/kg i.p.; monkeys, 0.16 mg/kg i.m.) from saline in a two-lever drug discrimination task on a fixed-ratio 32 (FR 32) schedule of food presentation. After reliable discrimination control of lever choice was established, generalization tests were conducted every third day. Test periods consisted of a 2-min period during which responding on either lever was reinforced (rats) or responding was recorded but not reinforced (monkeys). The PCP dose-response determination preceded generalization testing with other compounds. Dose-effect curves for each drug for percent drug-lever appropriate responding and for suppression of operant responding during sessions were analyzed by linear regression. In Experiment II the discriminative stimulus properties of PCP and five other arylcycloalkylamines were investigated in squirrel monkeys .Generalization testing was conducted with PCP, PCE, TCP, 1-(1-phenylcyclohexyl) morpholine (PCM), 1-(1-phenylcyclohexyl) pyrroldine (PHP), and ketamine. All drugs produced dose-dependent PCP-appropriate responding. The dose necessary to suppress operant responding to fifty percent of vehicle rates was 3 to 8 times larger than the ED50 for drug-lever appropriate responding. Experiments III, IV and VI were designed to explore similarities between the discriminative stimulus properties of PCP and a series of structurally dissimilar compounds. In Experiment III the discriminative stimulus properties of dexoxadrol and etoxadrol, both 2-(2,2-substituted 1,3 dioxolan-4-yl) piperdines, were studied in squirrel monkeys. Both compounds generalized to PCP in a dose-dependent manner. The dose necessary to suppress operant responding to fifty percent of vehicle rates was 3 to 8 times larger than the ED5O dose · for drug-lever appropriate responding. In Experiment IV the discriminative stimulus properties of stereoisomers of N-allylnormetazocine, a benzomorphan opioid with psychotomimetic properties, were investigated in squirrel monkeys and rats. In both species, the (+) isomer and the racemic mixture produced dose dependent PCP-appropriate responding. The (-) isomer did not produce PCP-appropriate responding, however it was more potent than the (+) isomer in overall response rate suppression. High doses of naloxone (rats, 30 mg/kg;monkeys, 1.0 and 3.0 mg/kg) did not block the drug lever appropriate responding or response rate suppression produced by either isomer of N -allynormetazocine. In Experiment V the discriminative stimulus properties of ketamine stereoisomers were investigated in rats. Both isomers and the racemic form of ketamine produced drug-lever appropriate responding and decreased response rate in a dose-dependent manner. There was no significant potency difference between (±)-ketamine and either of the isomers for either of these measures. The stereoselectivity of the discriminative stimulus properties of cyclazocine, another opioid of the benzomorphan series, in squirrel monkeys was explored in Experiment VI. The (+) isomer produced dose dependent PCP-appropriate responding . The (-) isomer and the racemic mixture did not produce PCP-appropriate responding at any of the doses tested. The (-) isomer was 300 times more potent than the (+) isomer in overall response rate suppression. The work presented in this thesis suggests that PCP belongs to a unique class of drugs which can have a wide variety of chemical structures. The overalp in the behavioral pharmacology of PCP and the psychotomimetic opioids of the benzomorphan series is probably due to the activity of the (+) isomers of these compounds

Practical considerations for estimating clinical trial accrual periods: application to a multi-center effectiveness study

Abstract Background Adequate participant recruitment is vital to the conduct of a clinical trial. Projected recruitment rates are often over-estimated, and the time to recruit the target population (accrual period) is often under-estimated. Methods This report illustrates three approaches to estimating the accrual period and applies the methods to a multi-center, randomized, placebo controlled trial undergoing development. Results Incorporating known sources of accrual variation can yield a more justified estimate of the accrual period. Simulation studies can be incorporated into a clinical trial's planning phase to provide estimates for key accrual summaries including the mean and standard deviation of the accrual period. Conclusion The accrual period of a clinical trial should be carefully considered, and the allocation of sufficient time for participant recruitment is a fundamental aspect of planning a clinical trial.</p

Efficacy of Ketamine in the Treatment of Substance Use Disorders: A Systematic Review

Background: Despite advances in behavioral and pharmacotherapy interventions, substance use disorders (SUDs) are frequently refractory to treatment. Glutamatergic dysregulation has received increasing attention as one common neuropathology across multiple substances of abuse. Ketamine is a potent N-methyl-D-aspartate (NMDA) glutamatergic receptor antagonist which has been found to be effective in the treatment of severe depression. Here we review the literature on the efficacy of ketamine in the treatment of SUDs.Methods: A systematic review of the PubMed, Scopus, and ClinicalTrials.gov databases was undertaken to identify completed and ongoing human studies of the effectiveness of ketamine in the treatment of SUDs between January 1997 and January 2018.Results and conclusion: Seven completed studies were identified. Two studies focused on alcohol use disorder, two focused on cocaine use disorder, and three focused on opioid use disorder. Both cocaine studies found improvements in craving, motivation, and decreased cocaine use rates, although studies were limited by small sample sizes, a homogeneous population and short follow-up. Studies of alcohol and opioid use disorders found improvement in abstinence rates in the ketamine group, with significant between-group effects noted for up to two years following a single infusion, although these were not placebo-controlled trials. These results suggest that ketamine may facilitate abstinence across multiple substances of abuse and warrants broader investigation in addiction treatment. We conclude with an overview of the six ongoing studies of ketamine in the treatment of alcohol, cocaine, cannabis, and opioid use disorders and discuss future directions in this emerging area of research

Laboratory-induced cue reactivity among individuals with prescription opioid dependence

Prescription opioid (PO) dependence is a critical health problem. Although examination of drug cue reactivity paradigms has advanced the understanding of risk factors for relapse for a variety of substances (e.g., cocaine, alcohol, nicotine), no PO specific drug cue paradigm has been developed. The current study addressed this gap in the literature and evaluated the ability of a newly developed PO drug cue paradigm to elicit subjective, physiological, and neuroendocrine changes among PO-dependent participants (n = 20) as compared to controls (n = 17). The drug cue paradigm included an induction script, viewing and handling paraphernalia (e.g., bottle of oxycontin pills, pill crusher) and watching a video depicting people using POs as well as places related to POs (e.g., pharmacies). Consistent with hypotheses, the PO group demonstrated significant pre- to post-cue increases on subjective ratings of craving, difficulty resisting POs, stress, and anger. The control group did not demonstrate significant changes on any of the subjective measures. Both the PO group and the control group evidenced significant pre- to post-cue increases in physiological responses (e.g., blood pressure, skin conductance), as expected given the arousing nature of the drug cue stimuli. The PO group, but not the control group, evidenced a significant pre- to post-cue increase in heart rate and salivary cortisol levels. The development and validation of a drug cue paradigm for POs may help inform future research and treatment development efforts for patients with PO dependence

A global survey on changes in the supply, price, and use of illicit drugs and alcohol, and related complications during the 2020 COVID-19 pandemic

Background and Aims : COVID-19 has infected more than 77 million people worldwide and impacted the lives of many more, with a particularly devastating impact on vulnerable populations, including people with substance use disorders (SUDs). Quarantines, travel bans, regulatory changes, social distancing, and "lockdown" measures have affected drug and alcohol supply chains and subsequently their availability, price, and use patterns, with possible downstream effects on presentations of SUDs and demand for treatment. Given the lack of multicentric epidemiologic studies, we conducted a rapid global survey within the International Society of Addiction Medicine (ISAM) network in order to understand the status of substance-use patterns during the current pandemic. Design : Cross-sectional survey. Setting : Worldwide. Participants : Starting on April 4, 2020 during a 5-week period, the survey received 185 responses from 77 countries. Measurements : To assess addiction medicine professionals' perceived changes in drug and alcohol supply, price, use pattern, and related complications during the COVID-19 pandemic. Findings : Participants reported (among who answered "decreased" or "increased") a decrease in drug supply (69.0%) and at the same time an increase in price (95.3%) globally. With respect to changes in use patterns, an increase in alcohol (71.7%), cannabis (63.0%), prescription opioids (70.9%), and sedative/hypnotics (84.6%) use was reported, while the use of amphetamines (59.7%), cocaine (67.5%), and opiates (58.2%) was reported to decrease overall. Conclusions : The global report on changes in the availability, use patterns, and complications of alcohol and drugs during the COVID-19 pandemic should be considered in making new policies and in developing mitigating measures and guidelines during the current pandemic (and probable future ones) in order to minimize risks to people with SUD.Publisher PDFPeer reviewe

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment