U-47700: A Clinical Review of the Literature.

BACKGROUND: U-47700 is a synthetic opioid developed by The Upjohn Company in the 1970s, which has recently appeared in the news and medical literature due to its toxicity. Currently, there are no clinical trial data assessing the safety of U-47700. OBJECTIVE: To describe the signs and symptoms of ingestion, laboratory testing, and treatment modalities for U-47700 intoxication. DISCUSSION: We searched PubMed, Embase, Web of Science, and EBSCO for articles using the term "U-47700" and "47700." The following inclusion criteria were used: had to be in English; full text; must involve humans; must be either a randomized control trial, prospective trial, retrospective analysis, case series, or case report; and must include clinical findings at presentation. We identified and extracted data from relevant articles. Ten relevant articles were included with 16 patients. Patients that died after overdose with U-47700 typically presented to the hospital with pulmonary edema. Patients who survived an overdose presented with decreased mental status and decreased respiratory rate suggestive of an opioid toxidrome. Patients also commonly had tachycardia. Immunoassays failed to identify U-47700, and the identification of U-47700 required the use of chromatographic and spectral techniques. CONCLUSION: We report the first clinical review of U-47700 intoxication.

A Psychonaut's Experience of Intoxication with Multiple Classes of Drugs Including Novel Psychoactive Substance 2-fluorodeschloroketamine: Case Report and Urinary Analysis.

Novel psychoactive substances have emerged as drugs of abuse. 2-Fluorodeschloroketamine (2-FDCK) is a ketamine derivative that can be purchased online for as little as $12 per gram. We report the case of a patient with a history of polysubstance use presenting after insufflation of 2-FDCK, with subsequent confirmation of metabolites in the patient's urine. A 28-year-old man presented to the Emergency Department in a dissociated state. He recovered well with supportive care, and described during interview his experience of substance use including the novel psychoactive substance 2-FDCK. A urine sample was sent for analysis and 2-FDCK metabolites were isolated. This case is concerning because 2-FDCK is a relatively new agent that has not yet been reported in the United States. It is easy to obtain over the internet and has significant abuse potential.

AH-7921: A review of previously published reports.

AH-7921 is a synthetic opioid that was developed in the early 1970s. It has resulted in several fatal and nonfatal intoxications, despite not having approval from the US Food and Drug Administration. To date, AH-7921 is listed as a schedule I drug, and there have been no clinical trials exploring the safety of AH-7921. Herein, we provide an analysis of existing case reports available in the literature regarding AH-7921. We searched PubMed, Scopus, Web of Science, and EBSCO for articles (up until December 2017) using the terms "AH-7921" and "AH7921." In total, 48 articles were identified, and 5 articles were included in our review. A total of 14 cases were found, of which 13 resulted in fatalities. The oral route of administration was reported in two cases, and most cases reported use of concomitant pharmaceutical agents. Pulmonary edema was the most common finding postmortem among deceased cases, with nine of the cases having heavier lungs. Overall, fatalities occurred with low and high concentrations of AH-7921 in the femoral blood. We strongly encourage toxicology screenings for this novel opioid to be included when an overdose of an opioid of unknown nature is suggested.

Addressing Hazards from Unscheduled Novel Psychoactive Substances as Research Chemicals: The Case of U-50488.

Increased experimentation with easily accessible synthetic opioids is posing a hazard to the public. We discuss one such synthetic opioid, U-50488. Much is unknown about U-50488; however, due to its structural similarity to U-47700, there is possible risk associated with its use. Curtailing the use of synthetic opioids such as U-50488 will require a concerted effort targeting multiple problems.

U-47700: An Emerging Threat.

Illicit opioid use continues to be an ever-growing problem in the United States. The rise of synthetic opioids is an emerging threat that is beginning to draw attention over the past few years. Herein, we present an overview of the rise of a synthetic opioid known as U-47700. We describe U-47700's history, legal status, ease of obtainment, consequences of its use, and a proposal to increase the awareness of this synthetic opioid.

To Dab or Not to Dab: Rising Concerns Regarding the Toxicity of Cannabis Concentrates.

Cannabis use is steadily rising in the United States. As the popularity of marijuana rises, new varieties of cannabis-related products are becoming available. Dabs are cannabis concentrates gaining notoriety for their significant amounts of tetrahydrocannabinol (THC) that are ultimately vaporized and inhaled for their effect. Herein, we provide an overview of recent cases of dabbing to bring awareness to the clinicians, of the significant adverse effects associated with dabs including psychosis, neurotoxicity, and cardiotoxicity.

On the Horizon: The Synthetic Opioid U-49900.

Synthetic opioid use continues to be a problem in the United States. New designer opioids continue to be released as "research chemicals" by vendors, leading to widespread use and potentially devastating consequences. U-49900 is a new synthetic opioid with limited clinical data available. Herein, we provide an overview of U-49900, the anecdotal accounts of U-49900 use that clinicians need to be made aware of, and a call for the federal government to take immediate action in curtailing the use of U-49900.

Analysis of U-47700, a Novel Synthetic Opioid, in Human Urine by LC-MS-MS and LC-QToF.

The illicit drug market has rapidly evolved from synthetic cannabinoids to cathinone derivatives and now a new emerging threat of synthetic opioids. These compounds were mostly developed by pharmaceutical companies during drug discovery. The new psychoactive substances are not routinely covered in drug screening and may go undetected. Recently fentanyl analogous, AH-7921, MT-45 and now U-47700 have been encountered in clinical and forensic casework. U-47700 is gaining popularity on drug user forms as a legal alternative to heroin. It is a µ-receptor agonist that is part of the trans-1-2-diamine opioid analgesic drug class developed by The Upjohn Company in an attempt to develop a non-addicting analgesic. A LC-MS-MS method was developed and validated to detect and quantify U-47700. Additional analysis was conducted with an LC-QToF to identify the presence of the parent drug and metabolites. A total of four cases have been evaluated by the LC-MS-MS methodology which has an analytical range of 1-1,250 ng/mL and limit of detection of 1 ng/mL. The concentration of U-47700 in urine specimens ranged from below the limit of quantification to 224 ng/mL. The ToF analysis detected the presence of suspected phase I demethylated metabolites that may assist future analysis of this compound. The prevalence of designer opioids in casework highlights the importance of analysis for new psychoactive substances. Traditional opiates/opioids were not detected in the presented cases, but the available case histories revealed an opioid toxidrome. These findings suggest that U-47700 drug may cause significant morbidity and mortality within the United States as an emerging drug threat.

Constructing Carbon Fiber Motion-Detection Loops for Simultaneous EEG-fMRI.

One of the most significant impediments to high-quality EEG recorded in an MRI scanner is subject motion. Availability of motion artifact sensors can substantially improve the quality of the recorded EEG. In the study of epilepsy, it can also dramatically increase the confidence that one has in discriminating true epileptiform activity from artifact. This is due both to the reduction in artifact and the ability to visually inspect the motion sensor signals when reading the EEG, revealing whether or not head motion is present. We have previously described the use of carbon fiber loops for detecting and correcting artifact in EEG acquired simultaneously with MRI. The loops, attached to the subject's head, are electrically insulated from the scalp. They provide a simple and direct measure of specific artifact that is contaminating the EEG, including both subject motion and residual artifact arising from magnetic field gradients applied during MRI. Our previous implementation was used together with a custom-built EEG-fMRI system that differs substantially from current commercially available EEG-fMRI systems. The present technical note extends this work, describing in more detail how to construct the carbon fiber motion-detection loops, and how to interface them with a commercially available simultaneous EEG-fMRI system. We hope that the information provided may help those wishing to utilize a motion-detection/correction solution to improve the quality of EEG recorded within an MRI scanner.

Fatality involving complications of bupivacaine toxicity and hypersensitivity reaction.

This case represents unusual findings of elevated bupivacaine and tryptase concentrations following local anesthetic, bupivacaine, administered as a scalene nerve block for elective rotator cuff repair surgery. Following bupivacaine injection, the patient exhibited almost immediate seizure activity, bradycardia, and cardiac arrest. Resuscitative efforts including cardiopulmonary bypass restored a cardiac rhythm. However, the clinical medical status of the patient progressively declined and he died 7 h following administration of the local anesthetic. Autopsy revealed several abnormalities of the heart including cardiomegaly, myocardial bridging, and lipomatous hypertrophy of the intraatrial septum, which may have contributed to bradycardia and arrhythmia. Postmortem toxicology results revealed elevated bupivacaine and tryptase concentrations. Elevated postmortem bupivacaine concentrations 7 h following administration and abrupt onset of seizures indicate unintentional intravascular injection instead of nerve and tissue infiltration. An elevated postmortem tryptase concentration points to the possibility of a hypersensitivity reaction to bupivacaine.

Quantitation of cocaine, benzoylecgonine, ecgonine methyl ester, and cocaethylene in urine and blood using gas chromatography-mass spectrometry (GC-MS).

Cocaine, a stimulant, is a commonly abused drug. Cocaine and its metabolites are measured in various biological specimens for clinical and forensic purposes. Urine or plasma or serum is spiked with deuterated internal standards cocaine-d3, benzoylecgonine-d3, ecgonine methyl ester-d3, and cocaethylene-d3 and buffered with phosphate buffer. The drugs in the sample are extracted by cation-exchange solid phase extraction. The drugs from the solid phase cartridge are eluted and the eluent is dried under the stream of nitrogen. The residue is incubated with pentafluoropropionic acid anhydride and pentafluoropropanol to form pentafluoropropionyl derivatives of ecgonine methyl ester and benzoylecgonine. Cocaine and cocaethylene are refractory to derivatization. The extract is dried, reconstituted in ethyl acetate, and injected into gas chromatography mass-spectrometry analyzer. Quantitation of the drugs in the samples is made, using selected ion monitoring, from a 3-point calibration curve.

Measurement and reduction of motion and ballistocardiogram artefacts from simultaneous EEG and fMRI recordings.

Recording the electroencephalogram (EEG) during functional magnetic resonance imaging (fMRI) permits the identification of haemodynamic changes associated with EEG events. However, subject motion within the MR scanner can cause unpredictable and frustrating artefacts on the EEG that may appear focally, bilaterally or unilaterally and can sometimes be confused for epileptiform activity. Motion may arise from a number of sources: small involuntary cardiac-related body movements (ballistocardiogram); acoustic vibrations due to the scanner machinery; and voluntary subject movements. Here we describe a new real-time technique for removing ballistocardiogram (BCG) and movement artefact from EEG recordings in the MR scanner using a novel method for recording subject motion. We record the current induced in a number of wire loops, attached to a cap worn by the subject, due to motion in the static magnetic field of the scanner (Faraday's Law). This is the same process that leads to the motion artefacts on the EEG, and hence these signals are ideally suited to filtering these artefacts from the EEG. Our filter uses a linear adaptive technique based upon the Recursive Least Squares (RLS) algorithm. We demonstrate in both simulations and real EEG recordings from epilepsy patients that our filter significantly reduces the artefact power whilst preserving the underlying EEG signal.

Further steps toward direct magnetic resonance (MR) imaging detection of neural action currents: optimization of MR sensitivity to transient and weak currents in a conductor.

The characteristics of an MRI technique that could be used for direct detection of neuronal activity are investigated. It was shown that magnitude imaging using echo planar imaging can detect transient local currents. The sensitivity of this method was thoroughly investigated. A partial k-space EPI acquisition with homodyne reconstruction was found to increase the signal change. A unique sensitivity to the position of the current pulse within the imaging sequence was demonstrated with the greatest signal change occurring when the current pulse coincides with the acquisition of the center lines of k-space. The signal change was shown to be highly sensitive to the spatial position of the current conductor relative to the voxel. Furthermore, with the use of optimization of spatial and temporal placement of the current pulse, the level of signal change obtained at this lower limit of current detectability was considerably magnified. It was possible to detect a current of 1.7 microA applied for 20 ms with an imaging time of 1.8 min. The level of sensitivity observed in our study brings us closer to that theoretically required for the detection of action currents in nerves.