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Journal of Comparative Physiology. A,... May 2024The channels commonly responsible for maintaining cell resting membrane potentials are referred to as K2P (two-P-domain K subunit) channels. These K ion channels...
The channels commonly responsible for maintaining cell resting membrane potentials are referred to as K2P (two-P-domain K subunit) channels. These K ion channels generally remain open but can be modulated by their local environment. These channels are classified based on pharmacology, pH sensitivity, mechanical stretch, and ionic permeability. Little is known about the physiological nature of these K2P channels in invertebrates. Acidic conditions depolarize neurons and muscle fibers, which may be caused by K2P channels given that one subtype can be blocked by acidic conditions. Doxapram is used clinically as a respiratory aid known to block acid-sensitive K2P channels; thus, the effects of doxapram on the muscle fibers and synaptic transmission in larval Drosophila and crawfish were monitored. A dose-dependent response was observed via depolarization of the larval Drosophila muscle and an increase in evoked synaptic transmission, but doxapram blocked the production of action potentials in the crawfish motor neuron and had a minor effect on the resting membrane potential of the crawfish muscle. This indicates that the nerve and muscle tissues in larval Drosophila and crawfish likely express different K2P channel subtypes. Since these organisms serve as physiological models for neurobiology and physiology, it would be of interest to further investigate what types of K2P channel are expressed in these tissues. (212 words).
PubMed: 38802613
DOI: 10.1007/s00359-024-01705-6 -
Heart Rhythm Apr 2024
PubMed: 38574786
DOI: 10.1016/j.hrthm.2024.03.1809 -
Archives of Disease in Childhood. Fetal... Mar 2024
PubMed: 38503483
DOI: 10.1136/archdischild-2024-327012 -
Archives of Disease in Childhood. Fetal... Jun 2024To assess the long-term neurodevelopmental impact of doxapram for treating apnoea of prematurity.
OBJECTIVE
To assess the long-term neurodevelopmental impact of doxapram for treating apnoea of prematurity.
DESIGN
Secondary analysis of the French national cohort study EPIPAGE-2. Recruitment took place in 2011. A standardised neurodevelopmental assessment was performed at age 5-6 years. A 2:1 propensity score matching was used to control for the non-randomised assignment of doxapram treatment.
SETTING
Population-based cohort study.
PATIENTS
All children born before 32 weeks' gestation alive at age 5-6 years.
INTERVENTIONS
Blind and standardised assessment by trained neuropsychologists and paediatricians at age 5-6 years.
MAIN OUTCOME MEASURES
Neurodevelopmental outcomes at age 5-6 years assessed by trained paediatricians and neuropsychologists: cerebral palsy, developmental coordination disorders, IQ and behavioural difficulties. A composite criterion for overall neurodevelopmental disabilities was built.
RESULTS
The population consisted of 2950 children; 275 (8.6%) received doxapram. Median (IQR) gestational age was 29.4 (27.6-30.9) weeks. At age 5-6 years, complete neurodevelopmental assessment was available for 60.3% (1780 of 2950) of children and partial assessment for 10.6% (314 of 2950). In the initial sample, children receiving doxapram had evidence of greater clinical severity than those not treated. Doxapram treatment was associated with overall neurodevelopmental disabilities of any severity (OR 1.43, 95% CI 1.07 to 1.92, p=0.02). Eight hundred and twenty-one children were included in the 2:1 matched sample. In this sample, perinatal characteristics of both groups were similar and doxapram treatment was not associated with overall neurodevelopmental disabilities (OR 1.09, 95% CI 0.76 to 1.57, p=0.63).
CONCLUSIONS
In children born before 32 weeks' gestation, doxapram treatment for apnoea of prematurity was not associated with neurodevelopmental disabilities.
Topics: Humans; Child, Preschool; Female; Male; Infant, Newborn; Infant, Premature, Diseases; Infant, Premature; Doxapram; Child; Apnea; Neurodevelopmental Disorders; Gestational Age; Cerebral Palsy; Developmental Disabilities; France; Cohort Studies
PubMed: 38228381
DOI: 10.1136/archdischild-2023-326170 -
Journal of Clinical Medicine Dec 2023Necrotizing enterocolitis (NEC) is a critical gastrointestinal emergency with substantial morbidity and mortality risks, especially for very low-birth-weight (VLBW)... (Review)
Review
Necrotizing enterocolitis (NEC) is a critical gastrointestinal emergency with substantial morbidity and mortality risks, especially for very low-birth-weight (VLBW) infants, and unclear multifactorial pathophysiology. Whether common treatments for VLBW infants increase the NEC risk remains controversial. Indomethacin (utilized for patent ductus arteriosus) offers benefits but is concerning because of its vasoconstrictive impact on NEC susceptibility. Similarly, corticosteroids used to treat bronchopulmonary dysplasia may increase vulnerability to NEC by compromising immunity and altering the mesenteric blood flow. Histamine-2 receptor blockers (used to treat gastric bleeding) may inadvertently promote NEC by affecting bacterial colonization and translocation. Doxapram (used to treat apnea) poses a risk of gastrointestinal disturbance via gastric acid hypersecretion and circulatory changes. Glycerin enemas aid meconium evacuation but disrupt microbial equilibrium and trigger stress-related effects associated with the NEC risk. Prolonged antibiotic use may unintentionally increase the NEC risk. Blood transfusions for anemia can promote NEC via interactions between the immune response and ischemia-reperfusion injury. Probiotics for NEC prevention are associated with concerns regarding sepsis and bacteremia. Amid conflicting evidence, this review unveils NEC risk factors related to treatments for VLBW infants, offers a comprehensive overview of the current research, and guides personalized management strategies, thereby elucidating this clinical dilemma.
PubMed: 38202069
DOI: 10.3390/jcm13010062 -
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 -
Seminars in Fetal & Neonatal Medicine Oct 2023This chapter focuses on the pharmacological management of newborn infants in the peri-extubation period to reduce the risk of re-intubation and prolonged mechanical... (Review)
Review
This chapter focuses on the pharmacological management of newborn infants in the peri-extubation period to reduce the risk of re-intubation and prolonged mechanical ventilation. Drugs used to promote respiratory drive, reduce the risk of apnoea, reduce lung inflammation and avoid bronchospasm are critically assessed. When available, Cochrane reviews and randomised trials are used as the primary sources of evidence. Methylxanthines, particularly caffeine, are well studied and there is accumulating evidence to guide clinicians on the timing and dosage that may be used. Efficacy and safety for doxapram, steroids, adrenaline and salbutamol are summarised. Management of term infants, extubation following surgery, accidental and complicated extubation and the use of cuffed endotracheal tubes are presented. Overall, caffeine is the only drug with a substantial evidence base, proven to increase the likelihood of successful extubation in preterm infants; no drugs are needed to facilitate extubation in most term infants. Future studies might further define the role of caffeine in late preterm infants and evaluate medications for post-extubation stridor, bronchospasm or apnoea not responsive to methylxanthines.
Topics: Infant, Newborn; Humans; Infant, Premature; Caffeine; Apnea; Ventilator Weaning; Bronchial Spasm; Intermittent Positive-Pressure Ventilation; Airway Extubation
PubMed: 38030435
DOI: 10.1016/j.siny.2023.101490 -
The Cochrane Database of Systematic... Oct 2023Apnea of prematurity is a common problem in preterm infants that may have significant consequences on their development. Methylxanthines (aminophylline, theophylline,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Apnea of prematurity is a common problem in preterm infants that may have significant consequences on their development. Methylxanthines (aminophylline, theophylline, and caffeine) are effective in the treatment of apnea of prematurity. Doxapram is used as a respiratory stimulant in cases refractory to the methylxanthine treatment.
OBJECTIVES
To evaluate the benefits and harms of doxapram administration on the incidence of apnea and other short-term and longer-term clinical outcomes in preterm infants.
SEARCH METHODS
We used standard, extensive Cochrane search methods. The latest search date was March 2023.
SELECTION CRITERIA
We included randomized controlled trials (RCTs) assessing the role of doxapram in prevention and treatment of apnea of prematurity and prevention of reintubation in preterm infants (less than 37 weeks' gestation). We included studies comparing doxapram with either placebo or methylxanthines as a control group, or when doxapram was used as an adjunct to methylxanthines and compared to methylxanthines alone as a control group. We included studies of doxapram at any dose and route.
DATA COLLECTION AND ANALYSIS
We used standard Cochrane methods. Our primary outcomes were clinical apnea, need for positive pressure ventilation after initiation of treatment, failed apnea reduction after two to seven days, and failed extubation (defined as unable to wean from invasive intermittent positive pressure ventilation [IPPV] and extubate or reintubation for IPPV within one week). We used GRADE to assess the certainty of evidence for each outcome.
MAIN RESULTS
We included eight RCTs enrolling 248 infants. Seven studies (214 participants) provided data for meta-analysis. Five studied doxapram for treatment of apnea in preterm infants. Three studied doxapram to prevent reintubation in preterm infants. None studied doxapram in preventing apnea in preterm infants. All studies administered doxapram intravenously as continuous infusions. Two studies used doxapram as an adjunct to aminophylline compared to aminophylline alone and one study as an adjunct to caffeine compared to caffeine alone. When used to treat apnea, compared to no treatment, doxapram may result in a slight reduction in failed apnea reduction (risk ratio [RR] 0.45, 95% confidence interval [CI] 0.20 to 1.05; 1 study, 21 participants; low-certainty evidence). The evidence is very uncertain about the effect of doxapram on need for positive pressure ventilation after initiation of treatment (RR 0.31, 95% CI 0.01 to 6.74; 1 study, 21 participants; very low-certainty evidence). Doxapram may result in little to no difference in side effects causing cessation of therapy (0 events in both groups; risk difference [RD] 0.00, 95% CI -0.17 to 0.17; 1 study, 21 participants; low-certainty evidence). Compared to alternative treatment, the evidence is very uncertain about the effect of doxapram on failed apnea reduction (RR 1.35, 95% CI 0.53 to 3.45; 4 studies, 84 participants; very low-certainty evidence). The evidence is very uncertain about the effect of doxapram on need for positive pressure ventilation after initiation of treatment (RR 2.40, 95% CI 0.11 to 51.32; 2 studies, 37 participants; very-low certainty evidence; note 1 study recorded 0 events in both groups. Thus, the RR and CIs were calculated from 1 study rather than 2). Doxapram may result in little to no difference in side effects causing cessation of therapy (0 events in all groups; RD 0.00, 95% CI -0.15 to 0.15; 37 participants; 2 studies; low-certainty evidence). As adjunct therapy to methylxanthine, the evidence is very uncertain about the effect of doxapram on failed apnea reduction after two to seven days (RR 0.08, 95% CI 0.01 to 1.17; 1 study, 10 participants; very low-certainty evidence). No studies reported on clinical apnea, chronic lung disease at 36 weeks' postmenstrual age (PMA), death at any time during initial hospitalization, long-term neurodevelopmental outcomes in the three comparisons, and need for positive pressure ventilation and side effects when used as adjunct therapy to methylxanthine. In studies to prevent reintubation, when compared to alternative treatment, the evidence is very uncertain about the effect of doxapram on failed extubation (RR 0.43, 95% CI 0.10 to 1.83; 1 study, 25 participants; very low-certainty evidence). As adjunct therapy to methylxanthine, doxapram may result in a slight reduction in 'clinical apnea' after initiation of treatment (RR 0.36, 95% CI 0.13 to 0.98; 1 study, 56 participants; low-certainty evidence). Doxapram may result in little to no difference in failed extubation (RR 0.92, 95% CI 0.52 to 1.62; 1 study, 56 participants; low-certainty evidence). The evidence is very uncertain about the effect of doxapram on side effects causing cessation of therapy (RR 6.42, 95% CI 0.80 to 51.26; 2 studies, 85 participants; very low-certainty evidence). No studies reported need for positive pressure ventilation, chronic lung disease at 36 weeks' PMA, long-term neurodevelopmental outcomes in the three comparisons; failed extubation when compared to no treatment; and clinical apnea, death at any time during initial hospitalization, and side effects when compared to no treatment or alternative treatment. We identified two ongoing studies, one conducted in Germany and one in multiple centers in the Netherlands and Belgium.
AUTHORS' CONCLUSIONS
In treating apnea of prematurity, doxapram may slightly reduce failure in apnea reduction when compared to no treatment and there may be little to no difference in side effects against both no treatment and alternative treatment. The evidence is very uncertain about the need for positive pressure ventilation when compared to no treatment or alternative treatment and about failed apnea reduction when used as alternative or adjunct therapy to methylxanthine. For use to prevent reintubation, doxapram may reduce apnea episodes when administered in adjunct to methylxanthine, but with little to no difference in failed extubation. The evidence is very uncertain about doxapram's effect on death when used as adjunct therapy to methylxanthine and about failed extubation when used as alternative or adjunct therapy to methylxanthine. There is a knowledge gap about the use of doxapram as a therapy to prevent apnea. More studies are needed to clarify the role of doxapram in the treatment of apnea of prematurity, addressing concerns about long-term outcomes. The ongoing studies may provide useful data.
Topics: Infant, Newborn; Humans; Doxapram; Apnea; Caffeine; Aminophylline; Infant, Premature; Lung Diseases
PubMed: 37877431
DOI: 10.1002/14651858.CD014145.pub2 -
Trials Oct 2023Apnoea of prematurity (AOP) is one of the most common diagnoses among preterm infants. AOP often leads to hypoxemia and bradycardia which are associated with an...
BACKGROUND
Apnoea of prematurity (AOP) is one of the most common diagnoses among preterm infants. AOP often leads to hypoxemia and bradycardia which are associated with an increased risk of death or disability. In addition to caffeine therapy and non-invasive respiratory support, doxapram might be used to reduce hypoxemic episodes and the need for invasive mechanical ventilation in preterm infants, thereby possibly improving their long-term outcome. However, high-quality trials on doxapram are lacking. The DOXA-trial therefore aims to investigate the safety and efficacy of doxapram compared to placebo in reducing the composite outcome of death or severe disability at 18 to 24 months corrected age.
METHODS
The DOXA-trial is a double blinded, multicentre, randomized, placebo-controlled trial conducted in the Netherlands, Belgium and Canada. A total of 396 preterm infants with a gestational age below 29 weeks, suffering from AOP unresponsive to non-invasive respiratory support and caffeine will be randomized to receive doxapram therapy or placebo. The primary outcome is death or severe disability, defined as cognitive delay, cerebral palsy, severe hearing loss, or bilateral blindness, at 18-24 months corrected age. Secondary outcomes are short-term neonatal morbidity, including duration of mechanical ventilation, bronchopulmonary dysplasia and necrotising enterocolitis, hospital mortality, adverse effects, pharmacokinetics and cost-effectiveness. Analysis will be on an intention-to-treat principle.
DISCUSSION
Doxapram has the potential to improve neonatal outcomes by improving respiration, but the safety concerns need to be weighed against the potential risks of invasive mechanical ventilation. It is unknown if the use of doxapram improves the long-term outcome. This forms the clinical equipoise of the current trial. This international, multicentre trial will provide the needed high-quality evidence on the efficacy and safety of doxapram in the treatment of AOP in preterm infants.
TRIAL REGISTRATION
ClinicalTrials.gov NCT04430790 and EUDRACT 2019-003666-41. Prospectively registered on respectively June and January 2020.
Topics: Humans; Infant; Infant, Newborn; Bronchopulmonary Dysplasia; Caffeine; Doxapram; Gestational Age; Infant, Premature; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Double-Blind Method
PubMed: 37817255
DOI: 10.1186/s13063-023-07683-5 -
Biology Jul 2023Lipopolysaccharides (LPS) associated with Gram-negative bacteria are one factor responsible for triggering the mammalian immune response. Blocking the action of LPS is...
Lipopolysaccharides (LPS) associated with Gram-negative bacteria are one factor responsible for triggering the mammalian immune response. Blocking the action of LPS is key to reducing its downstream effects. However, the direct action of LPS on cells is not yet fully addressed. LPS can have rapid, direct effects on cells in the absence of a systemic immune response. Recent studies have shown that doxapram, a blocker of a subset of K2P channels, also blocks the acute actions of LPS. Doxapram was evaluated to determine if such action also occurs at glutamatergic synapses in which it is known that LPS can increase synaptic transmission. Doxapram at 5 mM first enhanced synaptic transmission, then reduced synaptic response, while 10 mM rapidly blocked transmission. Doxapram at 5 mM blocked the excitatory response induced by LPS. Enhancing synaptic transmission with LPS and then applying LPS combined with doxapram also resulted in retarding the response of LPS. It is possible doxapram and LPS are mediated via a similar receptor or cellular responses. The potential of designing pharmacological compounds with a similar structure to doxapram and determining the binding of such compounds can aid in addressing the acute, direct actions by LPS on cells.
PubMed: 37626932
DOI: 10.3390/biology12081046