Dataset Information

Computational Systems Pharmacology-Target Mapping for Fentanyl-Laced Cocaine Overdose.

ABSTRACT: The United States of America is fighting against one of its worst-ever drug crises. Over 900 people a week die from opioid- or heroin-related overdoses, while millions more suffer from opioid prescription addiction. Recently, drug overdoses caused by fentanyl-laced cocaine specifically are on the rise. Due to drug synergy and an increase in side effects, polydrug addiction can cause more risk than addiction to a single drug. In the present work, we systematically analyzed the overdose and addiction mechanism of cocaine and fentanyl. First, we applied our established chemogenomics knowledgebase and machine-learning-based methods to map out the potential and known proteins, transporters, and metabolic enzymes and the potential therapeutic target(s) for cocaine and fentanyl. Sequentially, we looked into the detail of (1) the addiction to cocaine and fentanyl by binding to the dopamine transporter and the ? opioid receptor (DAT and ?OR, respectively), (2) the potential drug-drug interaction of cocaine and fentanyl via p-glycoprotein (P-gp) efflux, (3) the metabolism of cocaine and fentanyl in CYP3A4, and (4) the physiologically based pharmacokinetic (PBPK) model for two drugs and their drug-drug interaction at the absorption, distribution, metabolism, and excretion (ADME) level. Finally, we looked into the detail of JWH133, an agonist of cannabinoid 2-receptor (CB2) with potential as a therapy for cocaine and fentanyl overdose. All these results provide a better understanding of fentanyl and cocaine polydrug addiction and future drug abuse prevention.

SUBMITTER: Cheng J

PROVIDER: S-EPMC6733029 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Computational Systems Pharmacology-Target Mapping for Fentanyl-Laced Cocaine Overdose.

Cheng Jin J Wang Siyi S Lin Weiwei W Wu Nan N Wang Yuanqiang Y Chen Maozi M Xie Xiang-Qun XQ Feng Zhiwei Z

ACS chemical neuroscience 20190715 8

The United States of America is fighting against one of its worst-ever drug crises. Over 900 people a week die from opioid- or heroin-related overdoses, while millions more suffer from opioid prescription addiction. Recently, drug overdoses caused by fentanyl-laced cocaine specifically are on the rise. Due to drug synergy and an increase in side effects, polydrug addiction can cause more risk than addiction to a single drug. In the present work, we systematically analyzed the overdose and addict ...[more]

PMID: 31257858

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Project description:BackgroundDrug overdose mortality continues to increase, now driven by fentanyl. Prevention tools such as naloxone and medications to treat opioid use disorder are not sufficient to control overdose rates; additional strategies are urgently needed.ObjectiveWe sought to adapt a behavioral intervention to prevent opioid overdose (repeated-dose behavioral intervention to reduce opioid overdose [REBOOT]) that had been successfully piloted in San Francisco, California, United States, to the setting of Boston, Massachusetts, United States, and the era of fentanyl for a full efficacy trial.MethodsWe used the assessment, decision, adaptation, production, topical experts, integration, training, and testing (ADAPT-ITT) framework for intervention adaptation. We first identified opioid overdose survivors who were actively using opioids as the population of interest and REBOOT as the intervention to be adapted. We then performed theater testing and elicited feedback with 2 focus groups (n=10) in Boston in 2018. All participants had used opioids that were not prescribed to them in the past year and experienced an opioid overdose during their lifetime. We incorporated focus group findings into our initial draft of the adapted REBOOT intervention. The adapted intervention was reviewed by 3 topical experts, and their feedback was integrated into a subsequent draft. We trained study staff on the intervention and made final refinements based on internal piloting. This paper describes the overall ADAPT-ITT process for intervention adaptation, as well as a qualitative analysis of the focus groups. Working independently, 2 authors (VMM and JA) reviewed the focus group transcripts and coded them for salient and common themes using the constant comparison method, meeting to discuss any discrepancies until consensus was reached. Codes and themes were then mapped onto the REBOOT counseling steps.ResultsFocus group findings contributed to substantial changes in the counseling intervention to better address fentanyl overdose risk. Participants described the widespread prevalence of fentanyl and said that, although they tried to avoid it, avoidance was becoming impossible. Using alone and lower opioid tolerance were identified as contributors to overdose risk. Slow shots or tester shots were acceptable and considered effective to reduce risk. Naloxone was considered an effective reversal strategy. Although calling emergency services was not ruled out, participants described techniques to prevent the arrival of police on the scene. Expert review and internal piloting improved the intervention manual through increased participant centeredness, clarity, and usability.ConclusionsWe successfully completed the ADAPT-ITT approach for an overdose prevention intervention, using theater testing with people who use opioids to incorporate the perspectives of people who use drugs into a substance use intervention. In the current crisis, overdose prevention strategies must be adapted to the context of fentanyl, and innovative strategies must be deployed, including behavioral interventions.Trial registrationClinicalTrials.gov NCT03838510; https://clinicaltrials.gov/ct2/show/NCT03838510.

Project description:More than 50 million adults in America suffer from chronic pain. Opioids are commonly prescribed for their effectiveness in relieving many types of pain. However, excessive prescribing of opioids can lead to abuse, addiction, and death. Non-steroidal anti-inflammatory drugs (NSAIDs), another major class of analgesic, also have many problematic side effects including headache, dizziness, vomiting, diarrhea, nausea, constipation, reduced appetite, and drowsiness. There is an urgent need for the understanding of molecular mechanisms that underlie drug abuse and addiction to aid in the design of new preventive or therapeutic agents for pain management. To facilitate pain related small-molecule signaling pathway studies and the prediction of potential therapeutic target(s) for the treatment of pain, we have constructed a comprehensive platform of a pain domain-specific chemogenomics knowledgebase (Pain-CKB) with integrated data mining computing tools. Our new computing platform describes the chemical molecules, genes, proteins, and signaling pathways involved in pain regulation. Pain-CKB is implemented with a friendly user interface for the prediction of the relevant protein targets and analysis and visualization of the outputs, including HTDocking, TargetHunter, BBB predictor, and Spider Plot. Combining these with other novel tools, we performed three case studies to systematically demonstrate how further studies can be conducted based on the data generated from Pain-CKB and its algorithms and tools. First, systems pharmacology target mapping was carried out for four FDA approved analgesics in order to identify the known target and predict off-target interactions. Subsequently, the target mapping outcomes were applied to build physiologically based pharmacokinetic (PBPK) models for acetaminophen and fentanyl to explore the drug-drug interaction (DDI) between this pair of drugs. Finally, pharmaco-analytics was conducted to explore the detailed interaction pattern of acetaminophen reactive metabolite and its hepatotoxicity target, thioredoxin reductase.

Dataset Information

Computational Systems Pharmacology-Target Mapping for Fentanyl-Laced Cocaine Overdose.

Publications

Computational Systems Pharmacology-Target Mapping for Fentanyl-Laced Cocaine Overdose.

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