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BMC Anesthesiology Nov 2019Painless gastrointestinal endoscopy under intravenous propofol anesthesia is widely applied in the clinical scenario. Despite the good sedation and elimination of... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Painless gastrointestinal endoscopy under intravenous propofol anesthesia is widely applied in the clinical scenario. Despite the good sedation and elimination of anxiety that propofol provides, low SpO may also result. Doxapram is a respiratory stimulant with a short half-life. The primary aim of this study was to investigate the effects of doxapram on alleviating low SpO induced by the combination of propofol and fentanyl during painless gastrointestinal endoscopy.
METHODS
In this prospective study, patients scheduled for painless gastrointestinal endoscopy were randomly assigned to group D or S with 55 patients per group. Initially, both groups received a combination of propofol and fentanyl. Patients in group D received 50 mg doxapram after propofol injection, while patients in group S received an equal volume of saline. Vital signs of the patients, propofol dose, examination duration, and incidences of low SpO were recorded.
RESULTS
There were no statistical differences in propofol consumption and examination duration between the two groups. Twenty-six patients in group S experienced low SpO versus 10 in group D (P = 0.001). Nineteen patients in group S underwent oxygenation with a face mask in contrast to 8 in group D (P = 0.015). Eighteen patients in group S were treated with jaw lifting compared to 5 in group D (P = 0.002). Four patients in group S underwent assisted respiration compared to 2 in group D (without statistical difference). The average oxygen saturation in group S was significantly lower than that in group D at 1, 2 and 3 min after propofol injection (P < 0.001, P = 0.001 and P = 0.020, respectively). There were no statistical differences in oxygen saturation at other time points. There were no statistical differences in MAP and HR (except for the time point of 1 min after the induction) between the two groups.
CONCLUSIONS
Low dose of doxapram can effectively alleviate low SpO in painless gastrointestinal endoscopy with intravenous propofol, without affecting propofol consumption, examination duration, MAP, or HR.
TRAIL REGISTRATION
The study was approved by the Institutional Ethics Committee of Clinical and New Technology of Wuxi People's Hospital on 20th July, 2018 (KYLLH2018029) and registered in the Chinese Clinical Trial Register on 16th August, 2018 (ChiCTR1800017832).
Topics: Adult; Anesthetics, Intravenous; Double-Blind Method; Doxapram; Endoscopy, Gastrointestinal; Female; Fentanyl; Humans; Male; Middle Aged; Oxygen; Propofol; Prospective Studies; Respiratory System Agents; Time Factors
PubMed: 31757206
DOI: 10.1186/s12871-019-0860-1 -
International Journal of Molecular... Dec 2022Bacterial septicemia is commonly induced by Gram-negative bacteria. The immune response is triggered in part by the secretion of bacterial endotoxin lipopolysaccharide...
Bacterial septicemia is commonly induced by Gram-negative bacteria. The immune response is triggered in part by the secretion of bacterial endotoxin lipopolysaccharide (LPS). LPS induces the subsequent release of inflammatory cytokines which can result in pathological conditions. There is no known blocker to the receptors of LPS. The larval muscle is an amendable model to rapidly screen various compounds that affect membrane potential and synaptic transmission such as LPS. LPS induces a rapid hyperpolarization in the body wall muscles and depolarization of motor neurons. These actions are blocked by the compound doxapram (10 mM), which is known to inhibit a subtype of the two-P-domain K+ channel (K2P channels). However, the K2P channel blocker PK-THPP had no effect on the larval muscle at 1 and 10 mM. These channels are activated by chloroform, which also induces a rapid hyperpolarization of these muscles, but the channels are not blocked by doxapram. Likewise, chloroform does not block the depolarization induced by doxapram. LPS blocks the postsynaptic glutamate receptors on muscle. Pre-exposure to doxapram reduces the LPS block of these ionotropic glutamate receptors. Given that the larval body wall muscles are depolarized by doxapram and hyperpolarized by chloroform, they offer a model to begin pharmacological profiling of the K2P subtype channels with the potential of identifying blockers for the receptors to mitigate the actions of the Gram-negative endotoxin LPS.
Topics: Animals; Doxapram; Lipopolysaccharides; Chloroform; Synaptic Transmission; Drosophila
PubMed: 36555429
DOI: 10.3390/ijms232415787 -
Frontiers in Bioscience (Landmark... Nov 2023Mutations in the gene are among the most frequent genetic alterations in various cancers, and inhibiting RAS signaling has shown promising results in treating solid...
Identification of Potential Inhibitors Targeting GTPase-Kirsten RAt Sarcoma Virus (K-Ras) Driven Cancers via E-Pharmacophore-Based Virtual Screening and Drug Repurposing Approach.
BACKGROUND
Mutations in the gene are among the most frequent genetic alterations in various cancers, and inhibiting RAS signaling has shown promising results in treating solid tumors. However, finding effective drugs that can bind to the RAS protein remains challenging. This drove us to explore new compounds that could inhibit tumor growth, particularly in cancers that harbor K-Ras mutations.
METHODS
Our study used bioinformatic techniques such as E-pharmacophore virtual screening, molecular simulation, principal component analysis (PCA), extra precision (XP) docking, and ADMET analyses to identify potential inhibitors for K-Ras mutants G12C and G12D.
RESULTS
In our study, we discovered that inhibitors such as afatinib, osimertinib, and hydroxychloroquine strongly inhibit the G12C mutant. Similarly, hydroxyzine, zuclopenthixol, fluphenazine, and doxapram were potent inhibitors for the G12D mutant. Notably, all six of these molecules exhibit a high binding affinity for the H95 cryptic groove present in the mutant structure. These molecules exhibited a unique affinity mechanism at the molecular level, which was further enhanced by hydrophobic interactions. Molecular simulations and PCA revealed the formation of stable complexes within switch regions I and II. This was particularly evident in three complexes: G12C-osimertinib, G12D-fluphenazine, and G12D-zuclopenthixol. Despite the dynamic nature of switches I and II in K-Ras, the interaction of inhibitors remained stable. According to QikProp results, the properties and descriptors of the selected molecules fell within an acceptable range compared to sotorasib.
CONCLUSIONS
We have successfully identified potential inhibitors of the K-Ras protein, laying the groundwork for the development of targeted therapies for cancers driven by K-Ras mutations.
Topics: Humans; Protein Binding; Proto-Oncogene Proteins p21(ras); Pharmacophore; Clopenthixol; Drug Repositioning; Fluphenazine; Early Detection of Cancer; ras Proteins; Neoplasms; Molecular Dynamics Simulation
PubMed: 38062837
DOI: 10.31083/j.fbl2811288 -
BMJ Open Sep 2021Apnoea affects 85% of premature infants under 34 weeks of age and would be an important risk factor for subsequent neuropsychological disorders. Currently, premature...
Protocol of controlled odorant stimulation for reducing apnoeic episodes in premature newborns: a randomised open-label Latin-square study with independent evaluation of the main endpoint (PREMODEUR).
INTRODUCTION
Apnoea affects 85% of premature infants under 34 weeks of age and would be an important risk factor for subsequent neuropsychological disorders. Currently, premature children with life-threatening apnoeas receive stimulants such as methylxanthines (mainly, caffeine) or doxapram (an analeptic unlicensed in children under 15). However, these products have undesirable effects (hyperarousal, irritability, sleep disorders, tachycardia) and are not always effective because apnoea does persist in some premature newborns. Previous studies have indicated that odorant stimulation, a non-invasive intervention, may stimulate the respiratory rhythm. The objective of the present protocol is to reduce the occurrence of apnoeic episodes in premature newborns by controlled odorant stimulation added to current pharmacological treatments.
METHODS AND ANALYSIS
The project is a randomised open-label Latin-square trial with independent evaluation of the main endpoint. It will include 60 preterm neonates from two university hospital neonatal intensive care units over 2 years (2021-2023). Each newborn will receive no (S0), sham (S1) or real olfactory stimulation (S2) in random order. During S2, three distinct odorants (mint, grapefruit and vanilla) will be delivered successively, in puffs, over 24 hours. Mint and grapefruit odours stimulate the main and the trigeminal olfactory pathways, whereas vanilla odour stimulates only the main olfactory pathway. A statistical analysis will compare the incidence of apnoeic episodes during S1 versus S2 using a mixed effects Poisson model.
ETHICS AND DISSEMINATION
Ethical approval was obtained from the Comité de Protection des Personnes Île-de-France XI (# 2017-AO13-50-53). The results will be disseminated through various scientific meetings, specialised peer-reviewed journals and, whenever possible, posted on appropriate public websites.
TRIAL REGISTRATION NUMBER
NCT02851979; Pre-results.
Topics: Apnea; Child; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Intensive Care Units, Neonatal; Odorants; Randomized Controlled Trials as Topic
PubMed: 34518252
DOI: 10.1136/bmjopen-2020-047141 -
The Canadian Veterinary Journal = La... Feb 2020This case highlights the successful recovery to discharge of a hypothermic cat in cardiac arrest, with minimal lasting clinical signs. Immediately after resuscitation,...
This case highlights the successful recovery to discharge of a hypothermic cat in cardiac arrest, with minimal lasting clinical signs. Immediately after resuscitation, the cat was blind and non-ambulatory paraparetic. Within 4 days, the cat became fully ambulatory, but vision loss remains. We believe that the cat's hypothermia likely contributed to this successful outcome. Other factors which may have played a role in the cat's recovery were the administration of mannitol and anti-seizure medications. Key clinical message: We share learning points regarding re-warming rates for hypothermic patients and the use of Doxapram for stimulation of the central respiratory center.
Topics: Animals; Cardiopulmonary Resuscitation; Cat Diseases; Cats; Heart Arrest; Hypoglycemic Agents; Hypothermia
PubMed: 32020934
DOI: No ID Found -
Sleep Jan 2021Obstructive sleep apnea (OSA) occurs exclusively during sleep due to reduced tongue motor activity. Withdrawal of excitatory inputs to the hypoglossal motor nucleus...
Modulation of TASK-1/3 channels at the hypoglossal motoneuron pool and effects on tongue motor output and responses to excitatory inputs in vivo: implications for strategies for obstructive sleep apnea pharmacotherapy.
Obstructive sleep apnea (OSA) occurs exclusively during sleep due to reduced tongue motor activity. Withdrawal of excitatory inputs to the hypoglossal motor nucleus (HMN) from wake to sleep contributes to this reduced activity. Several awake-active neurotransmitters with inputs to the HMN (e.g. serotonin [5-HT]) inhibit K+ leak mediated by TASK-1/3 channels on hypoglossal motoneurons, leading to increased neuronal activity in vitro. We hypothesize that TASK channel inhibition at the HMN will increase tongue muscle activity in vivo and modulate responses to 5-HT. We first microperfused the HMN of anesthetized rats with TASK channel inhibitors: doxapram (75 μM, n = 9), A1899 (25 μM, n = 9), ML365 (25 μM, n = 9), acidified artificial cerebrospinal fluid (ACSF, pH = 6.25, n = 9); and a TASK channel activator terbinafine (50 μM, n = 9); all with and without co-applied 5-HT (10 mM). 5-HT alone at the HMN increased tongue motor activity (202.8% ± 45.9%, p < 0.001). However, neither the TASK channel inhibitors, nor activator, at the HMN changed baseline tongue activity (p > 0.716) or responses to 5-HT (p > 0.127). Tonic tongue motor responses to 5-HT at the HMN were also not different (p > 0.05) between ChAT-Cre:TASKf/f mice (n = 8) lacking TASK-1/3 channels on cholinergic neurons versus controls (n = 10). In freely behaving rats (n = 9), microperfusion of A1899 into the HMN increased within-breath phasic tongue motor activity in wakefulness only (p = 0.005) but not sleep, with no effects on tonic activity across all sleep-wake states. Together, the findings suggest robust maintenance of tongue motor activity despite various strategies for TASK channel manipulation targeting the HMN in vivo, and thus currently do not support this target and direction for potential OSA pharmacotherapy.
Topics: Animals; Hypoglossal Nerve; Mice; Motor Neurons; Rats; Rats, Wistar; Sleep Apnea, Obstructive; Tongue
PubMed: 32745213
DOI: 10.1093/sleep/zsaa144 -
Archives of Disease in Childhood. Fetal... Jan 2020During delayed umbilical cord clamping, the factors underpinning placental transfusion remain unknown. We hypothesised that reductions in thoracic pressure during...
INTRODUCTION
During delayed umbilical cord clamping, the factors underpinning placental transfusion remain unknown. We hypothesised that reductions in thoracic pressure during inspiration would enhance placental transfusion in spontaneously breathing preterm lambs.
OBJECTIVE
Investigate the effect of spontaneous breathing on umbilical venous flow and body weight in preterm lambs.
METHODS
Pregnant sheep were instrumented at 132-133 days gestational age to measure fetal common umbilical venous, pulmonary and cerebral blood flows as well as arterial and intrapleural (IP) pressures. At delivery, doxapram and caffeine were administered to promote breathing. Lamb body weights were measured continuously and breathing was assessed by IP pressure changes.
RESULTS
In 6 lambs, 491 out of 1117 breaths were analysed for change in body weight. Weight increased in 46.6% and decreased in 47.5% of breaths. An overall mean increase of 0.02±2.5 g per breath was calculated, and no net placental transfusion was observed prior to cord clamping (median difference in body weight 52.3 [-54.9-166.1] g, p=0.418). Umbilical venous (UV) flow transiently decreased with each inspiration, and in some cases ceased, before UV flow normalised during expiration. The reduction in UV flow was positively correlated with the standardised reduction in (IP) pressure, increasing by 109 mL/min for every SD reduction in IP pressure. Thus, the reduction in UV flow was closely related to inspiratory depth.
CONCLUSIONS
Spontaneous breathing had no net effect on body weight in preterm lambs at birth. UV blood flow decreased as inspiratory effort increased, possibly due to constriction of the inferior vena cava caused by diaphragmatic contraction, as previously observed in human fetuses.
Topics: Animals; Animals, Newborn; Blood Flow Velocity; Body Weight; Constriction; Disease Models, Animal; Female; Placental Circulation; Pregnancy; Premature Birth; Respiration; Sheep; Time Factors; Umbilical Cord; Umbilical Veins
PubMed: 31092674
DOI: 10.1136/archdischild-2018-316044 -
Archives of Disease in Childhood. Fetal... Mar 2024
PubMed: 38503483
DOI: 10.1136/archdischild-2024-327012 -
Neonatology 2020
Topics: Doxapram; Humans; Infant; Infant, Newborn; Infant, Premature; Retrospective Studies
PubMed: 32829326
DOI: 10.1159/000510058 -
Heart Rhythm Apr 2024
PubMed: 38574786
DOI: 10.1016/j.hrthm.2024.03.1809