scholarly journals Respiratory depression in rats induced by alcohol and barbiturate and rescue by ampakine CX717

2012 ◽  
Vol 113 (7) ◽  
pp. 1004-1011 ◽  
Author(s):  
Jun Ren ◽  
Xiuqing Ding ◽  
John J. Greer
Keyword(s):  
Respiratory Depression ◽  
Circulatory Support ◽  
Respiratory Drive ◽  
Drug Induced ◽  
Adult Rats ◽  
Respiratory Rhythmogenesis ◽  
Life Threatening ◽  
Preclinical And Clinical Studies

Barbiturate use in conjunction with alcohol can result in severe respiratory depression and overdose deaths. The mechanisms underlying the additive/synergistic actions were unresolved. Current management of ethanol-barbiturate-induced apnea is limited to ventilatory and circulatory support coupled with drug elimination. Based on recent preclinical and clinical studies of opiate-induced respiratory depression, we hypothesized that ampakine compounds may provide a treatment for other types of drug-induced respiratory depression. The actions of alcohol, pentobarbital, bicuculline, and the ampakine CX717, alone and in combination, were measured via 1) ventral root recordings from newborn rat brain stem-spinal cord preparations and 2) plethysmographic recordings from unrestrained newborn and adult rats. We found that ethanol caused a modest suppression of respiratory drive in vitro (50 mM) and in vivo (2 g/kg ip). Pentobarbital induced an ∼50% reduction in respiratory frequency in vitro (50 μM) and in vivo (28 mg/kg for pups and 56 mg/kg for adult rats ip). However, severe life-threatening apnea was induced by the combination of the agents in vitro and in vivo via activation of GABAA receptors, which was exacerbated by hypoxic (8% O2) conditions. Administration of the ampakine CX717 alleviated a significant component of the respiratory depression in vitro (50–150 μM) and in vivo (30 mg/kg ip). Bicuculline also alleviated ethanol-/pentobarbital-induced respiratory depression but caused seizure activity, whereas CX717 did not. These data demonstrated that ethanol and pentobarbital together caused severe respiratory depression, including lethal apnea, via synergistic actions that blunt chemoreceptive responses to hypoxia and hypercapnia and suppress central respiratory rhythmogenesis. The ampakine CX717 markedly reduced the severity of respiratory depression.

scholarly journals Coadministration of the AMPAKINE CX717 with Propofol Reduces Respiratory Depression and Fatal Apneas

2013 ◽  
Vol 118 (6) ◽  
pp. 1437-1445 ◽  
Author(s):  
Jun Ren ◽  
Floriane Lenal ◽  
Michael Yang ◽  
Xiuqing Ding ◽  
John J. Greer
Keyword(s):  
Respiratory Depression ◽  
Safety Margin ◽  
Adult Rats ◽  
Control Frequency ◽  
Rat Brainstem ◽  
Nerve Recordings ◽  
Working Heart

Abstract Background: Propofol (2,6-diisopropylphenol) is used for the induction and maintenance of anesthesia in human and veterinary medicine. Propofol’s disadvantages include the induction of respiratory depression and apnea. Here, the authors report a clinically feasible pharmacological solution for reducing propofol-induced respiratory depression via a mechanism that does not interfere with anesthesia. Specifically, they test the hypothesis that the AMPAKINE CX717, which has been proven metabolically stable and safe for human use, can prevent and rescue from propofol-induced severe apnea. Methods: The actions of propofol and the AMPAKINE CX717 were measured via (1) ventral root recordings from newborn rat brainstem–spinal cord preparations, (2) phrenic nerve recordings from an adult mouse in situ working heart–brainstem preparation, and (3) plethysmographic recordings from unrestrained newborn and adult rats. Results: In vitro, respiratory depression caused by propofol (2 μm, n = 11, mean ± SEM, 41±5% of control frequency, 63±5% of control duration) was alleviated by CX717 (n = 4, 50–150 μm). In situ, a decrease in respiratory frequency (44±9% of control), phrenic burst duration (66±7% of control), and amplitude (78±5% of control) caused by propofol (2 μm, n = 5) was alleviated by coadministration of CX717 (50 μm, n = 5). In vivo, pre- or coadministration of CX717 (20–25mg/kg) with propofol markedly reduced propofol-induced respiratory depression (n = 7; 20mg/kg) and propofol-induced lethal apnea (n = 6; 30mg/kg). Conclusions: Administration of CX717 before or in conjunction with propofol provides an increased safety margin against profound apnea and death.

scholarly journals Glial TLR4 signaling does not contribute to opioid-induced depression of respiration

2014 ◽  
Vol 117 (8) ◽  
pp. 857-868 ◽  
Author(s):  
Jennifer D. Zwicker ◽  
Yong Zhang ◽  
Jun Ren ◽  
Mark R. Hutchinson ◽  
Kenner C. Rice ◽  
...  
Keyword(s):  
Respiratory Depression ◽  
Respiratory Rhythm ◽  
Opioid Antagonist ◽  
Adult Rats ◽  
Opioid Receptor Agonist ◽  
Bath Application ◽  
The Central Nervous System ◽  
Tlr4 Antagonist

Opioids activate glia in the central nervous system in part by activating the toll-like receptor 4 (TLR4)/myeloid differentiation 2 (MD2) complex. TLR4/MD2-mediated activation of glia by opioids compromises their analgesic actions. Glial activation is also hypothesized as pivotal in opioid-mediated reward and tolerance and as a contributor to opioid-mediated respiratory depression. We tested the contribution of TLR4 to opioid-induced respiratory depression using rhythmically active medullary slices that contain the pre-Bötzinger Complex (preBötC, an important site of respiratory rhythm generation) and adult rats in vivo. Injection with DAMGO (μ-opioid receptor agonist; 50 μM) or bath application of DAMGO (500 nM) or fentanyl (1 μM) slowed frequency recorded from XII nerves to 40%, 40%, or 50% of control, respectively. This DAMGO-mediated frequency inhibition was unaffected by preapplication of lipopolysaccharides from Rhodobacter sphaeroides (a TLR4 antagonist, 2,000 ng/ml) or (+)naloxone (1–10 μM, a TLR4-antagonist). Bath application of (−)naloxone (500 nM; a TLR4 and μ-opioid antagonist), however, rapidly reversed the opioid-mediated frequency decrease. We also compared the opioid-induced respiratory depression in slices in vitro in the absence and presence of bath-applied minocycline (an inhibitor of microglial activation) and in slices prepared from mice injected (ip) 18 h earlier with minocycline or saline. Minocycline had no effect on respiratory depression in vitro. Finally, the respiratory depression evoked in anesthetized rats by tail vein infusion of fentanyl was unaffected by subsequent injection of (+)naloxone, but completely reversed by (−)naloxone. These data indicate that neither activation of microglia in preBötC nor TLR4/MD2-activation contribute to opioid-induced respiratory depression.

scholarly journals Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm-generating network

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Nathan A Baertsch ◽  
Nicholas E Bush ◽  
Nicholas J Burgraff ◽  
Jan-Marino Ramirez
Keyword(s):  
Transgenic Mice ◽  
Synaptic Transmission ◽  
Respiratory Depression ◽  
Opioid Receptor ◽  
In Silico ◽  
Pronounced Decrease ◽  
Life Threatening ◽  
Μ Opioid Receptor

The analgesic utility of opioid-based drugs is limited by the life-threatening risk of respiratory depression. Opioid-induced respiratory depression (OIRD), mediated by the μ-opioid receptor (MOR), is characterized by a pronounced decrease in the frequency and regularity of the inspiratory rhythm, which originates from the medullary preBӧtzinger Complex (preBӧtC). To unravel the cellular- and network-level consequences of MOR activation in the preBӧtC, MOR- expressing neurons were optogenetically identified and manipulated in transgenic mice in vitro and in vivo. Based on these results, a model of OIRD was developed in silico. We conclude that hyperpolarization of MOR-expressing preBӧtC neurons alone does not phenocopy OIRD. Instead, the effects of MOR activation are twofold: 1) pre-inspiratory spiking is reduced and 2) excitatory synaptic transmission is suppressed, thereby disrupting network-driven rhythmogenesis. These dual mechanisms of opioid action act synergistically to make the normally robust inspiratory rhythm generating network particularly prone to collapse when challenged with exogenous opioids.

scholarly journals Amnesic Concentrations of the Nonimmobilizer 1,2-Dichlorohexafluorocyclobutane (F6, 2N) and Isoflurane Alter Hippocampal θ Oscillations In Vivo 

2007 ◽  
Vol 106 (6) ◽  
pp. 1168-1176 ◽  
Author(s):  
Misha Perouansky ◽  
Harald Hentschke ◽  
Mark Perkins ◽  
Robert A. Pearce
Keyword(s):  
Theta Oscillations ◽  
Network Activity ◽  
Total Power ◽  
Theta Band ◽  
Drug Induced ◽  
Adult Rats ◽  
Common Basis ◽  
Depth Electrodes

Background Drug-induced temporary amnesia is one of the principal goals of general anesthesia. The nonimmobilizer 1,2-dichlorohexafluorocyclobutane (F6, also termed 2N) impairs hippocampus-dependent learning at relative, i.e., lipophilicity-corrected, concentrations similar to isoflurane. Hippocampal theta oscillations facilitate mnemonic processes in vivo and synaptic plasticity (a cellular model of memory) in vitro and are thought to represent a circuit level phenomenon that supports memory encoding. Therefore, the authors investigated the effects of F6 and isoflurane on theta oscillations (4-12 Hz). Methods Thirteen adult rats were implanted with multichannel depth electrodes to measure the microelectroencephalogram and were exposed to a range of concentrations of isoflurane and F6 spanning the concentrations that produce amnesia. Five of these animals also underwent control experiments without drug injection. The authors recorded the behavioral state and hippocampal field potentials. They confirmed the electrode location postmortem by histology. Results The tested concentrations for isoflurane and F6 ranged from 0.035% to 0.77% and from 0.5% to 3.6%, respectively. Isoflurane increased the fraction of time that the animals remained immobile, consistent with sedation, whereas F6 had the opposite effect. Electroencephalographic power in the theta band was less when the animals were immobile than when they explored their environment. F6 suppressed the power of oscillations in the theta band. Isoflurane slowed theta oscillations without reducing total power in the theta band. Conclusions Drug-induced changes in theta oscillations may be a common basis for amnesia produced by F6 and isoflurane. The different patterns suggest that these drugs alter network activity by acting on different molecular and/or cellular targets.

scholarly journals Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm-generating network

2021 ◽  
Author(s):  
Nathan A Baertsch ◽  
Nicholas E Bush ◽  
Nicholas J Burgraff ◽  
Jan-Marino Ramirez
Keyword(s):  
Transgenic Mice ◽  
Synaptic Transmission ◽  
Respiratory Depression ◽  
Opioid Receptor ◽  
In Silico ◽  
Pronounced Decrease ◽  
Life Threatening ◽  
Μ Opioid Receptor

AbstractThe analgesic utility of opioid-based drugs is limited by the life-threatening risk of respiratory depression. Opioid-induced respiratory depression (OIRD), mediated by the μ-opioid receptor (MOR), is characterized by a pronounced decrease in the frequency and regularity of the inspiratory rhythm, which originates from the medullary preBötzinger Complex (preBӧtC). To unravel the cellular- and network-level consequences of MOR activation in the preBötC, MOR-expressing neurons were optogenetically identified and manipulated in transgenic mice in vitro and in vivo. Based on these results, a model of OIRD was developed in silico. We conclude that hyperpolarization of MOR-expressing preBötC neurons alone does not phenocopy OIRD. Instead, the effects of MOR activation are twofold: 1) pre-inspiratory spiking is reduced and 2) excitatory synaptic transmission is suppressed, thereby disrupting network-driven rhythmogenesis. These dual mechanisms of opioid action act together to make the normally robust inspiratory-rhythm-generating network particularly prone to collapse when challenged with exogenous opioids.

scholarly journals Pathophysiology and Diagnosis of Drug-Induced Immune Thrombocytopenia

2020 ◽  
Vol 9 (7) ◽  
pp. 2212 ◽  
Author(s):  
Caroline Vayne ◽  
Eve-Anne Guéry ◽  
Jérôme Rollin ◽  
Tatiana Baglo ◽  
Rachel Petermann ◽  
...  
Keyword(s):  
Immune Thrombocytopenia ◽  
Clinical Syndrome ◽  
Severe Thrombocytopenia ◽  
Drug Induced ◽  
Platelet Factor ◽  
Life Threatening ◽  
Thrombotic Complications ◽  
Drug Dependent

Drug-induced immune thrombocytopenia (DITP) is a life-threatening clinical syndrome that is under-recognized and difficult to diagnose. Many drugs can cause immune-mediated thrombocytopenia, but the most commonly implicated are abciximab, carbamazepine, ceftriaxone, eptifibatide, heparin, ibuprofen, mirtazapine, oxaliplatin, penicillin, quinine, quinidine, rifampicin, suramin, tirofiban, trimethoprim-sulfamethoxazole, and vancomycin. Several different mechanisms have been identified in typical DITP, which is most commonly characterized by severe thrombocytopenia due to clearance and/or destruction of platelets sensitized by a drug-dependent antibody. Patients with typical DITP usually bleed when symptomatic, and biological confirmation of the diagnosis is often difficult because detection of drug-dependent antibodies (DDabs) in the patient’s serum or plasma is frequently not possible. This is in contrast to heparin-induced thrombocytopenia (HIT), which is a particular DITP caused in most cases by heparin-dependent antibodies specific for platelet factor 4, which can strongly activate platelets in vitro and in vivo, explaining why affected patients usually have thrombotic complications but do not bleed. In addition, laboratory tests are readily available to diagnose HIT, unlike the methods used to detect DDabs associated with other DITP that are mostly reserved for laboratories specialized in platelet immunology.

scholarly journals Modeling susceptibility to drug-induced long QT with a panel of subject-specific induced pluripotent stem cells

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Francesca Stillitano ◽  
Jens Hansen ◽  
Chi-Wing Kong ◽  
Ioannis Karakikes ◽  
Christian Funck-Brentano ◽  
...  
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
High Sensitivity ◽  
Cardiac Repolarization ◽  
Drug Induced ◽  
Life Threatening ◽  
Induced Pluripotent

A large number of drugs can induce prolongation of cardiac repolarization and life-threatening cardiac arrhythmias. The prediction of this side effect is however challenging as it usually develops in some genetically predisposed individuals with normal cardiac repolarization at baseline. Here, we describe a platform based on a genetically diverse panel of induced pluripotent stem cells (iPSCs) that reproduces susceptibility to develop a cardiotoxic drug response. We generated iPSC-derived cardiomyocytes from patients presenting in vivo with extremely low or high changes in cardiac repolarization in response to a pharmacological challenge with sotalol. In vitro, the responses to sotalol were highly variable but strongly correlated to the inter-individual differences observed in vivo. Transcriptomic profiling identified dysregulation of genes (DLG2, KCNE4, PTRF, HTR2C, CAMKV) involved in downstream regulation of cardiac repolarization machinery as underlying high sensitivity to sotalol. Our findings offer novel insights for the development of iPSC-based screening assays for testing individual drug reactions.

Electromagnetic field in Alzheimer’s disease: a literature review of recent preclinical and clinical studies

2020 ◽  
Vol 17 ◽  
Author(s):  
Reem Habib Mohamad Ali Ahmad ◽  
Marc Fakhoury ◽  
Nada Lawand
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
In Vivo Studies ◽  
Key Factors ◽  
Potential Benefits ◽  
Preclinical And Clinical Studies ◽  
The Brain

: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the progressive loss of neurons leading to cognitive and memory decay. The main signs of AD include the irregular extracellular accumulation of amyloidbeta (Aβ) protein in the brain and the hyper-phosphorylation of tau protein inside neurons. Changes in Aβ expression or aggregation are considered key factors in the pathophysiology of sporadic and early-onset AD and correlate with the cognitive decline seen in patients with AD. Despite decades of research, current approaches in the treatment of AD are only symptomatic in nature and are not effective in slowing or reversing the course of the disease. Encouragingly, recent evidence revealed that exposure to electromagnetic fields (EMF) can delay the development of AD and improve memory. This review paper discusses findings from in vitro and in vivo studies that investigate the link between EMF and AD at the cellular and behavioural level, and highlights the potential benefits of EMF as an innovative approach for the treatment of AD.

scholarly journals Enhancement of hepatic 4-hydroxylation of 25-hydroxyvitamin D3through CYP3A4 induction in vitro and in vivo: Implications for drug-induced osteomalacia

2013 ◽  
Vol 28 (5) ◽  
pp. 1101-1116 ◽  
Author(s):  
Zhican Wang ◽  
Yvonne S Lin ◽  
Leslie J Dickmann ◽  
Emma-Jane Poulton ◽  
David L Eaton ◽  
...  
Keyword(s):  
Drug Induced ◽  
Cyp3a4 Induction

Imidazolidinyl urea activates mast cells via MRGPRX2 to induce non-histaminergic allergy

2021 ◽  
Author(s):  
Jiapan Gao ◽  
Delu Che ◽  
Xueshan Du ◽  
Yi Zheng ◽  
Huiling Jing ◽  
...  
Keyword(s):  
Contact Dermatitis ◽  
Mast Cells ◽  
Pharmaceutical Products ◽  
Drug Induced ◽  
Inflammatory Infiltration ◽  
Local Inflammatory Response ◽  
Allergic Contact ◽  
G Protein Coupled

Abstract Imidazolidinyl urea (IU) is used as an antimicrobial preservative in cosmetic and pharmaceutical products. IU induces allergic contact dermatitis, however, the mechanism has not yet been elucidated. Mas-related G protein-coupled receptor-X2 (MRGPRX2) triggers drug-induced pseudo-allergic reactions. The aims of this study were to determine whether IU activated mast cells through MRGPRX2 to further trigger contact dermatitis. Wild-type (WT) and KitW-sh/HNihrJaeBsmJNju (MUT) mice were treated with IU to observe its effects on local inflammation and mast cells degranulation in vivo. Laboratory of allergic disease 2 cells were used to detect calcium mobilization and release of inflammatory mediators in vitro. WT mice showed a severe local inflammatory response and contact dermatitis, whereas only slight inflammatory infiltration was observed in MUT mice. Thus, MRGPRX2 mediated the IU-induced activation of mast cells. However, histamine, a typical allergen, was not involved in this process. Tryptase expressed by mast cells was the major non-histaminergic inflammatory mediator of contact dermatitis. IU induced anaphylactic reaction via MRGPRX2 and further triggering non-histaminergic contact dermatitis, which explained why antihistamines are clinically ineffective against some chronic dermatitis.

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