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 Ampakine CX717 Protects against Fentanyl-induced Respiratory Depression and Lethal Apnea in Rats

2009 ◽  
Vol 110 (6) ◽  
pp. 1364-1370 ◽  
Author(s):  
Jun Ren ◽  
Xiuqing Ding ◽  
Gregory D. Funk ◽  
John J. Greer
Keyword(s):  
Respiratory Depression ◽  
Lethal Dose ◽  
Cognitive Disorders ◽  
Opiate Receptor ◽  
Respiratory Frequency ◽  
Adult Rats ◽  
Analgesic Effects ◽  
Life Threatening ◽  
Nerve Recordings

Background The use of fentanyl as a potent analgesic is contradicted by marked respiratory depression among a subpopulation of patients. The commonly used approach of reversing fentanyl-induced respiratory depression with mu-opiate receptor antagonists such as naloxone has the undesirable effect of blocking analgesia. Here, the authors report a clinically feasible pharmacological solution for countering fentanyl-induced respiratory depression via a mechanism that does not interfere with analgesia. Specifically, to determine if the ampakine CX717, which has been proven metabolically stable and safe for human use, can prevent and rescue from severe fentanyl-induced apnea. Methods Plethsymographic recordings were performed from young and adult rats. Varying doses of fentanyl were administered either intraperitoneally or intravenously to induce moderate to life-threatening apneas. CX717 was administered either before or after fentanyl administration. In addition, phrenic nerve recordings were performed from in situ working heart brainstem preparations from juvenile rats. Results Preadministration of CX717 markedly attenuated fentanyl-induced respiratory depression. Postadministration of CX717 rescued animals from a lethal dose of fentanyl. Significantly, CX717 countered fentanyl-induced depression of respiratory frequency without suppressing analgesia. The effective dose of CX717 was in the range deemed safe on the basis of clinical trials examining its efficacy for cognitive disorders. In situ, fentanyl-induced depression in respiratory frequency and amplitude was alleviated by CX717. Conclusions CX717 is an agent that enhances the safety of using opiate drugs while preserving the analgesic effects. This advancement could significantly improve pain management in a variety of clinical settings.

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 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.

In vitro and in vivo polysaccharides assembly: ultrastructural and cytochemical study of growing plant cell wall components.

1978 ◽  
Vol 36 (2) ◽  
pp. 434-435
Author(s):  
D. Reis ◽  
B. Vian ◽  
J. C. Roland
Keyword(s):  
Cell Wall ◽  
Self Assembly ◽  
Plant Cell Wall ◽  
Higher Plants ◽  
Three Dimensional ◽  
Cytochemical Study ◽  
Wall Components

Wall morphogenesis in higher plants is a problem still open to controversy. Until now the possibility of a transmembrane control and the involvement of microtubules were mostly envisaged. Self-assembly processes have been observed in the case of walls of Chlamydomonas and bacteria. Spontaneous gelling interactions between xanthan and galactomannan from Ceratonia have been analyzed very recently. The present work provides indications that some processes of spontaneous aggregation could occur in higher plants during the formation and expansion of cell wall.Observations were performed on hypocotyl of mung bean (Phaseolus aureus) for which growth characteristics and wall composition have been previously defined.In situ, the walls of actively growing cells (primary walls) show an ordered three-dimensional organization (fig. 1). The wall is typically polylamellate with multifibrillar layers alternately transverse and longitudinal. Between these layers intermediate strata exist in which the orientation of microfibrils progressively rotates. Thus a progressive change in the morphogenetic activity occurs.

Evaluation of Structure-Controlled Silk Fibroin Coatings for Orthopedic Infection and In-Situ Osteogenesis: In Vitro and In Vivo

2020 ◽  
Author(s):  
Wenhao Zhou ◽  
Teng Zhang ◽  
Jianglong Yan ◽  
QiYao Li ◽  
Panpan Xiong ◽  
...  
Keyword(s):  
Silk Fibroin ◽  
Orthopedic Infection

Cytotoxicity Studies of Curcumin Loaded-Cockle Shell-Derived Calcium Carbonate Nanoparticles

2019 ◽  
Vol 09 ◽  
Author(s):  
Maryam Muhammad Mailafiya ◽  
Mohamad Aris Mohd Moklas ◽  
Kabeer Abubakar ◽  
Abubakar Danmaigoro ◽  
Samaila Musa Chiroma ◽  
...  
Keyword(s):  
Calcium Carbonate ◽  
Safety Margin ◽  
Bone Diseases ◽  
In Vivo Studies ◽  
Normal Cells ◽  
Cytotoxicity Studies ◽  
Standard Techniques ◽  
Cockle Shell

Background: Cockle shell-derived calcium carbonate nanoparticles (CSCaCO3NP) are natural biogenic inorganic material that is used in drug delivery mainly as a bone-remodeling agent as well as a delivery agent for various therapeutics against bone diseases. Curcumin possess wide safety margin and yet puzzled with the problem of poor bioavailability due to insolubility. Propounding in vitro and in vivo studies on toxicity assessments of newly synthesized nanoparticles are ongoing to overcome some crucial challenges regarding their safety administration. Nanotoxicology has paved ways for concise test protocols to monitor sequential events with regards to possible toxicity of newly synthesized nanomaterials. The development of nanoparticle with no or less toxic effect has gained tremendous attentions. Objective: This study aimed at evaluating the in vitro cytotoxic effect of curcumin-loaded cockle shell-derived calcium carbonate nanoparticles (Cur-CSCaCO3NP) and assessing its biocompatibility on normal cells using standard techniques of WST’s assay. Method: Standard techniques of WST’s assay was used for the evaluation of the biocompatibility and cytotoxicity. Result: The result showed that CSCaCO3NP and Cur-CSCaCO3NP possess minimal toxicity and high biocompatibility on normal cells even at higher dose of 500 µg/ml and 40 µg/ml respectively. Conclusion: CSCaCO3NP can be termed an excellent non-toxic nanocarrier for curcumin delivery. Hence, curcumin loaded cockle shell derived calcium carbonate nanoparticles (Cur-CSCaCO3NP) could further be assessed for various in vivo and in vitro therapeutic applications against various bone related ailments.

scholarly journals Development of In Situ Self-Assembly Nanoparticles to Encapsulate Lopinavir and Ritonavir for Long-Acting Subcutaneous Injection

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 904
Author(s):  
Irin Tanaudommongkon ◽  
Asama Tanaudommongkon ◽  
Xiaowei Dong
Keyword(s):  
Sustained Release ◽  
Trough Concentration ◽  
Self Assembly ◽  
Subcutaneous Injection ◽  
Drug Loading ◽  
Entrapment Efficiency ◽  
Long Acting

Most antiretroviral medications for human immunodeficiency virus treatment and prevention require high levels of patient adherence, such that medications need to be administered daily without missing doses. Here, a long-acting subcutaneous injection of lopinavir (LPV) in combination with ritonavir (RTV) using in situ self-assembly nanoparticles (ISNPs) was developed to potentially overcome adherence barriers. The ISNP approach can improve the pharmacokinetic profiles of the drugs. The ISNPs were characterized in terms of particle size, drug entrapment efficiency, drug loading, in vitro release study, and in vivo pharmacokinetic study. LPV/RTV ISNPs were 167.8 nm in size, with a polydispersity index of less than 0.35. The entrapment efficiency was over 98% for both LPV and RTV, with drug loadings of 25% LPV and 6.3% RTV. A slow release rate of LPV was observed at about 20% on day 5, followed by a sustained release beyond 14 days. RTV released faster than LPV in the first 5 days and slower than LPV thereafter. LPV trough concentration remained above 160 ng/mL and RTV trough concentration was above 50 ng/mL after 6 days with one subcutaneous injection. Overall, the ISNP-based LPV/RTV injection showed sustained release profiles in both in vitro and in vivo studies.

scholarly journals Establishment of MHHi001-A-5, a GCaMP6f and RedStar dual reporter human iPSC line for in vitro and in vivo characterization and in situ tracing of iPSC derivatives

2021 ◽  
Vol 52 ◽  
pp. 102206
Author(s):  
Alexandra Haase ◽  
Tim Kohrn ◽  
Veronika Fricke ◽  
Maria Elena Ricci Signorini ◽  
Merlin Witte ◽  
...  
Keyword(s):  
Ipsc Line ◽  
Dual Reporter ◽  
In Vivo Characterization ◽  
Human Ipsc

scholarly journals Enlisting the Ixodes scapularis Embryonic ISE6 Cell Line to Investigate the Neuronal Basis of Tick—Pathogen Interactions

Pathogens ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 70
Author(s):  
Lourdes Mateos-Hernández ◽  
Natália Pipová ◽  
Eléonore Allain ◽  
Céline Henry ◽  
Clotilde Rouxel ◽  
...  
Keyword(s):  
Cell Line ◽  
Peripheral Nerves ◽  
Ixodes Scapularis ◽  
Embryonic Cell ◽  
Cell Subpopulation ◽  
In Vivo Experiments

Neuropeptides are small signaling molecules expressed in the tick central nervous system, i.e., the synganglion. The neuronal-like Ixodes scapularis embryonic cell line, ISE6, is an effective tool frequently used for examining tick–pathogen interactions. We detected 37 neuropeptide transcripts in the I. scapularis ISE6 cell line using in silico methods, and six of these neuropeptide genes were used for experimental validation. Among these six neuropeptide genes, the tachykinin-related peptide (TRP) of ISE6 cells varied in transcript expression depending on the infection strain of the tick-borne pathogen, Anaplasma phagocytophilum. The immunocytochemistry of TRP revealed cytoplasmic expression in a prominent ISE6 cell subpopulation. The presence of TRP was also confirmed in A. phagocytophilum-infected ISE6 cells. The in situ hybridization and immunohistochemistry of TRP of I. scapularis synganglion revealed expression in distinct neuronal cells. In addition, TRP immunoreaction was detected in axons exiting the synganglion via peripheral nerves as well as in hemal nerve-associated lateral segmental organs. The characterization of a complete Ixodes neuropeptidome in ISE6 cells may serve as an effective in vitro tool to study how tick-borne pathogens interact with synganglion components that are vital to tick physiology. Therefore, our current study is a potential stepping stone for in vivo experiments to further examine the neuronal basis of tick–pathogen interactions.

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