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Chang HH, Zhang H, Latimore AD, Murray BP, D'Souza RR, Scovronick N, Gribble MO, Ebelt ST. Associations between short-term ambient temperature exposure and emergency department visits for amphetamine, cocaine, and opioid use in California from 2005 to 2019. ENVIRONMENT INTERNATIONAL 2023; 181:108233. [PMID: 37897873 PMCID: PMC10712015 DOI: 10.1016/j.envint.2023.108233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 09/12/2023] [Accepted: 09/25/2023] [Indexed: 10/30/2023]
Abstract
Substance use disorder is a growing public health challenge in the United States. People who use drugs may be more vulnerable to ambient heat due to the effects of drugs on thermoregulation and their risk environment. There have been limited population-based studies of ambient temperature and drug-related morbidity. We examined short-term associations between daily ambient temperature and emergency department (ED) visits for use or overdose of amphetamine, cocaine and opioids in California during the period 2005 to 2019. Daily ZIP code-level maximum, mean, and minimum temperature exposures were derived from 1-km data Daymet products. A time-stratified case-crossover design was used to estimate cumulative non-linear associations of daily temperature for lag days 0 to 3. Stratified analyses by patient sex, race, and ethnicity were also conducted. The study included over 3.4 million drug-related ED visits. We found positive associations between daily temperature and ED visits for all outcomes examined. An increase in daily mean temperature from the 50th to the 95th percentile was associated with ED visits for amphetamine use (OR = 1.072, 95% CI: 1.058, 1.086), cocaine use (OR = 1.044, 95% CI: 1.021, 1.068 and opioid use (OR = 1.041, 95% CI: 1.025, 1.057). Stronger positive associations were also observed for overdose: amphetamine overdose (OR = 1.150, 95% CI: 1.085, 1.218), cocaine overdose (OR = 1.159, 95% CI: 1.053, 1.276), and opioid overdose (OR = 1.079, 95% CI: 1.054, 1.106). In summary, people who use stimulants and opioids may be a subpopulation sensitive to short-term higher ambient temperature. Mitigating heat exposure can be considered in harm reduction strategies in response to the substance use epidemic and global climate change.
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Affiliation(s)
- Howard H Chang
- Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA, USA; Gangarosa Department of Environmental Health, Emory University, Atlanta, GA, USA.
| | - Haisu Zhang
- Gangarosa Department of Environmental Health, Emory University, Atlanta, GA, USA
| | - Amanda D Latimore
- Center for Addiction Research and Effective Solutions, American Institutes for Research, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Brian P Murray
- Emergency Medicine, Boonshoft School of Medicine, Wright State University, Dayton, OH, USA
| | - Rohan R D'Souza
- Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA, USA
| | - Noah Scovronick
- Gangarosa Department of Environmental Health, Emory University, Atlanta, GA, USA
| | - Matthew O Gribble
- Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Stefanie T Ebelt
- Gangarosa Department of Environmental Health, Emory University, Atlanta, GA, USA
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Vandeputte MM, Krotulski AJ, Walther D, Glatfelter GC, Papsun D, Walton SE, Logan BK, Baumann MH, Stove CP. Pharmacological evaluation and forensic case series of N-pyrrolidino etonitazene (etonitazepyne), a newly emerging 2-benzylbenzimidazole 'nitazene' synthetic opioid. Arch Toxicol 2022; 96:1845-1863. [PMID: 35477798 DOI: 10.1007/s00204-022-03276-4] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 03/14/2022] [Indexed: 11/25/2022]
Abstract
Novel synthetic opioids continue to emerge on recreational drug markets worldwide. In response to legislative bans on fentanyl analogues, non-fentanyl structural templates, such as 2-benzylbenzimidazoles ('nitazenes'), are being exploited to create new μ-opioid receptor (MOR) agonists. Here, we pharmacologically characterize an emerging cyclic analogue of etonitazene, called N-pyrrolidino etonitazene (etonitazepyne), using in vitro and in vivo methods. A series of analytically confirmed fatalities is described to complement preclinical findings. Radioligand binding assays in rat brain tissue revealed that N-pyrrolidino etonitazene has high affinity for MOR (Ki = 4.09 nM) over δ-opioid (Ki = 959 nM) and κ-opioid (Ki = 980 nM) receptors. In a MOR-β-arrestin2 activation assay, N-pyrrolidino etonitazene displayed high potency (EC50 = 0.348 nM), similar to etonitazene (EC50 = 0.360 nM), and largely exceeding the potencies of fentanyl (EC50 = 14.9 nM) and morphine (EC50 = 290 nM). When administered s.c. to male Sprague Dawley rats, N-pyrrolidino etonitazene induced opioid-like antinociceptive, cataleptic, and thermic effects. Its potency in the hot plate test (ED50 = 0.0017 mg/kg) was tenfold and 2,000-fold greater than fentanyl (ED50 = 0.0209 mg/kg) and morphine (ED50 = 3.940 mg/kg), respectively. Twenty-one overdose fatalities associated with N-pyrrolidino etonitazene were found to contain low blood concentrations of the drug (median = 2.2 ng/mL), commonly in the context of polysubstance use. N-Pyrrolidino etonitazene was reported as a cause of death in at least two cases, demonstrating toxicity in humans. We demonstrate that N-pyrrolidino etonitazene is an extremely potent MOR agonist that is likely to present high risk to users. Continued vigilance is required to identify and characterize emergent 2-benzylbenzimidazoles, and other non-fentanyl opioids, as they appear in the marketplace.
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Affiliation(s)
- Marthe M Vandeputte
- Laboratory of Toxicology, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium
| | - Alex J Krotulski
- Center for Forensic Science Research and Education, Fredric Rieders Family Foundation, Willow Grove, PA, 19090, USA
| | - Donna Walther
- Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA
| | - Grant C Glatfelter
- Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA
| | | | - Sara E Walton
- Center for Forensic Science Research and Education, Fredric Rieders Family Foundation, Willow Grove, PA, 19090, USA
| | - Barry K Logan
- Center for Forensic Science Research and Education, Fredric Rieders Family Foundation, Willow Grove, PA, 19090, USA
- NMS Labs, Horsham, PA, 19044, USA
| | - Michael H Baumann
- Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA
| | - Christophe P Stove
- Laboratory of Toxicology, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
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First identification, chemical analysis and pharmacological characterization of N-piperidinyl etonitazene (etonitazepipne), a recent addition to the 2-benzylbenzimidazole opioid subclass. Arch Toxicol 2022; 96:1865-1880. [PMID: 35449307 DOI: 10.1007/s00204-022-03294-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 03/24/2022] [Indexed: 12/20/2022]
Abstract
N-Piperidinyl etonitazene ('etonitazepipne') represents a recent addition to the rapidly expanding class of 2-benzylbenzimidazole 'nitazene' opioids. Following its first identification in an online-sourced powder and in biological samples from a patient seeking help for detoxification, this report details its in-depth chemical analysis and pharmacological characterization. Analysis of the powder via different techniques (LC-HRMS, GC-MS, UHPLC-DAD, FT-IR) led to the unequivocal identification of N-piperidinyl etonitazene. Furthermore, we report the first activity-based detection and analytical identification of N-piperidinyl etonitazene in authentic samples. LC-HRMS analysis revealed concentrations of 1.21 ng/mL in serum and 0.51 ng/mL in urine, whereas molecular networking enabled the tentative identification of various (potentially active) urinary metabolites. In addition, we determined that the extent of opioid activity present in the patient's serum was equivalent to the in vitro opioid activity exerted by 2.5-10 ng/mL fentanyl or 10-25 ng/mL hydromorphone in serum. Radioligand binding assays in rat brain tissue revealed that the drug binds with high affinity (Ki = 14.3 nM) to the µ-opioid receptor (MOR). Using a MOR-β-arrestin2 activation assay, we found that N-piperidinyl etonitazene is highly potent (EC50 = 2.49 nM) and efficacious (Emax = 183% versus hydromorphone) in vitro. Pharmacodynamic evaluation in male Sprague Dawley rats showed that N-piperidinyl etonitazene induces opioid-like antinociceptive, cataleptic, and thermic effects, its potency in the hot plate assay (ED50 = 0.0205 mg/kg) being comparable to that of fentanyl (ED50 = 0.0209 mg/kg), and > 190 times higher than that of morphine (ED50 = 3.940 mg/kg). Taken together, our findings indicate that N-piperidinyl etonitazene is a potent opioid with the potential to cause harm in users.
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Zhang YW, Zhang J, Hu JQ, Wen CL, Dai SY, Yang DF, Li LF, Wu QB. Neuraxial adjuvants for prevention of perioperative shivering during cesarean section: A network meta-analysis following the PRISMA guidelines. World J Clin Cases 2019; 7:2287-2301. [PMID: 31531322 PMCID: PMC6718794 DOI: 10.12998/wjcc.v7.i16.2287] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 06/25/2019] [Accepted: 07/20/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Perioperative shivering is clinically common during cesarean sections under neuraxial anesthesia, and several neuraxial adjuvants are reported to have preventive effects on it. However, the results of current studies are controversial and the effects of these neuraxial adjuvants remain unclear.
AIM To evaluate the effects of neuraxial adjuvants on perioperative shivering during cesarean sections, thus providing an optimal choice for clinical application.
METHODS A systematic review and network meta-analysis were conducted following the PRISMA (Preferred Reported Items for Systematic Review and Meta-analysis) guidelines. Analyses were performed using Review Manager 5.3 and Stata 14.0. We searched PubMed, EMBASE, Web of Science, and Cochrane Central databases for eligible clinical trials assessing the effects of neuraxial adjuvants on perioperative shivering and other adverse events during cesarean sections. Perioperative shivering was defined as the primary endpoint, and nausea, vomiting, pruritus, hypotension, and bradycardia were the secondary outcomes.
RESULTS Twenty-six studies using 9 neuraxial adjuvants for obstetric anesthesia during caesarean sections were included. The results showed that, compared with placebo, pethidine, fentanyl, dexmedetomidine, and sufentanil significantly reduced the incidence of perioperative shivering. Among the four neuraxial adjuvants, pethidine was the most effective one for shivering prevention (OR = 0.15, 95%CI: 0.07-0.35, surface under the cumulative ranking curve 83.9), but with a high incidence of nausea (OR = 3.15, 95%CI: 1.04-9.57) and vomiting (OR = 3.71, 95%CI: 1.81-7.58). The efficacy of fentanyl for shivering prevention was slightly inferior to pethidine (OR = 0.20, 95%CI: 0.09-0.43), however, it significantly decreased the incidence of nausea (OR = 0.34, 95%CI: 0.15-0.79) and vomiting (OR = 0.25, 95%CI: 0.11-0.56). In addition, compared with sufentanil, fentanyl showed no impact on haemodynamic stability and the incidence of pruritus.
CONCLUSION Pethidine, fentanyl, dexmedetomidine, and sufentanil appear to be effective for preventing perioperative shivering in puerperae undergoing cesarean sections. Considering the risk-benefit profiles of the included neuraxial adjuvants, fentanyl is probably the optimal choice.
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Affiliation(s)
- Yi-Wei Zhang
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau 999078, China
- Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
| | - Juan Zhang
- Department of Anesthesiology, First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou 310000, Zhejiang Province, China
| | - Jia-Qi Hu
- Department of Anesthesiology, First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou 310000, Zhejiang Province, China
- Department of Pain, Zhejiang Provincial People's Hospital, Hangzhou 310000, Zhejiang Province, China
| | - Chun-Lei Wen
- Department of Anesthesiology, First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou 310000, Zhejiang Province, China
| | - Shu-Yang Dai
- Department of Anesthesiology, Ruian People's Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Dan-Feng Yang
- Department of Anesthesiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Li-Fang Li
- Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
| | - Qi-Biao Wu
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau 999078, China
- Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
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δ-Opioid Receptor-Nrf-2-Mediated Inhibition of Inflammatory Cytokines in Neonatal Hypoxic-Ischemic Encephalopathy. Mol Neurobiol 2018; 56:5229-5240. [PMID: 30560518 DOI: 10.1007/s12035-018-1452-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2018] [Accepted: 12/07/2018] [Indexed: 12/11/2022]
Abstract
Neonatal hypoxic-ischemic encephalopathy (HIE) causes serious neurological disability; there are, however, currently few promising therapies for it. We have recently shown that δ-opioid receptor (DOR) is neuroprotective by downregulating TNF-α. Since hypoxia-ischemia (HI) triggers a robust inflammatory response, which exacerbates HI brain damage, we investigated, in this study, whether DOR activation could regulate inflammatory cytokine expression, thereby playing a protective effect on the neonatal brain under HI. Twenty-five neonatal rats were randomly divided into five groups: (1) control (control); (2) HI; (3) HI with saline (HI + NS); (4) DOR activation with UFP-512 (a potent and specific DOR agonist) under HI conditions (HI + U); and (5) DOR inhibition using NT treatment under HI conditions (HI + NT). The rats were sacrificed by decapitation at 24 h after HI, and their brains were rapidly removed for measurements. The protein expression of TNF-α, IL-6, ICAM-1, IL-10, IL-18, NQO-1, Nrf-2, and HO-1 was measured using Western blot. In the hemispheres exposed to HI, DOR activation significantly decreased the expressions of TNF-α, IL-6, and ICAM-1 in the cortex, while it significantly increased IL-10 and had no effect on IL-18 in the same region. In contrast, DOR had no appreciable effect on inflammatory cytokine expression in non-cortical tissues including hippocampal, subcortical, and cerebellar tissues. Moreover, HI stress triggered an upregulation of Nrf-2 nuclear protein as well as some of its downstream anti-inflammatory genes such as HO-1 and NQO-1 in the cortex, while DOR activation further augmented such a protective reaction against HI injury. DOR plays an important role in protecting against HI by regulating the expression of inflammatory and anti-inflammatory cytokines in the cortex, which is likely mediated by the Nrf-2/HO-1/NQO-1 signaling.
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