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Pediatric Pulmonology Jun 2022This study aimed to evaluate the change in the waveform pattern of the electrical activity of the diaphragm (Edi) following the administration of doxapram in extremely...
OBJECTIVE
This study aimed to evaluate the change in the waveform pattern of the electrical activity of the diaphragm (Edi) following the administration of doxapram in extremely preterm infants ventilated with neurally adjusted ventilatory assist (NAVA).
STUDY DESIGN
We conducted this retrospective cohort study in our neonatal intensive care unit between November 2019 and September 2021. The study participants were extremely preterm infants under the gestational age of 28 weeks who were ventilated with NAVA and administered doxapram. We collected the data of the Edi waveform pattern and calculated the proportion. To analyze the change in the proportion of the Edi waveform pattern, we compared the proportion of the data for 1 h before and after doxapram administration.
RESULTS
Ten extremely preterm infants were included. Almost all the patients' respiratory condition improved after doxapram administration. The ventilatory parameters-Edi peak, Edi minimum, peak inspiratory pressure, time in backup ventilation, and number of switches to backup ventilation-did not change significantly. However, the proportion of phasic pattern significantly increased (before: 46% vs. after: 72%; p < 0.05), whereas the central apnea pattern significantly decreased after doxapram administration (before: 31% vs. after: 8.3%; p < 0.05). The proportion of irregular low-voltage patterns tended to decrease, albeit with no significant changes.
CONCLUSION
Our results indicated that the proportion of Edi waveform patterns changed following doxapram administration. Edi waveform pattern analysis could be a sensitive indicator of effect with other intervention for respiratory conditions.
Topics: Diaphragm; Doxapram; Humans; Infant; Infant, Extremely Premature; Infant, Newborn; Interactive Ventilatory Support; Retrospective Studies
PubMed: 35274498
DOI: 10.1002/ppul.25889 -
Anesthesiology and Pain Medicine Feb 2016Postanaesthetic shivering is one of the most common unpleasant complications in patients.
BACKGROUND
Postanaesthetic shivering is one of the most common unpleasant complications in patients.
OBJECTIVES
The aim of this study was to compare the efficacy of doxapram, ketamine and meperidine in prevention of shivering after anaesthesia.
PATIENTS AND METHODS
In this randomized, double-blind clinical trial, 120 patients aged between 20 - 45 years old under general anaesthesia were enrolled. The patients were randomly allocated into one of three groups: group M received 20 mg meperidine (n = 40), group K received 0.25 mg/kg ketamine (n = 40) and group D received 0.25 mg/kg doxapram (n = 40). All of the drugs were administered intravenously. The core temperature, shivering, time of the first postoperative analgesic requirement, and some of the other side effects were recorded. Obtained data from the three groups were compared using one-way ANOVA and chi-square test.
RESULTS
Three patients (7.5%) of group K, four patients (10%) of group D and one patient (2.5%) of group M experienced shivering (P = 0.39). The interval to the first analgesic requirement significantly prolonged in the groups K and M compared to the group D (P < 0.001). No significant differences were identified in nausea and vomiting among the groups. No significant pharmaceutical adverse effects were observed in our study.
CONCLUSIONS
The results of this study showed that ketamine, doxapram and meperidine are equally effective in the prevention of postoperative shivering.
PubMed: 27110525
DOI: 10.5812/aapm.27515 -
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 -
Frontiers in Pharmacology 2021Atrial fibrillation (AF) is the most common sustained arrhythmia with a prevalence of up to 4% and an upwards trend due to demographic changes. It is associated with an... (Review)
Review
Atrial fibrillation (AF) is the most common sustained arrhythmia with a prevalence of up to 4% and an upwards trend due to demographic changes. It is associated with an increase in mortality and stroke incidences. While stroke risk can be significantly reduced through anticoagulant therapy, adequate treatment of other AF related symptoms remains an unmet medical need in many cases. Two main treatment strategies are available: rate control that modulates ventricular heart rate and prevents tachymyopathy as well as rhythm control that aims to restore and sustain sinus rhythm. Rate control can be achieved through drugs or ablation of the atrioventricular node, rendering the patient pacemaker-dependent. For rhythm control electrical cardioversion and pharmacological cardioversion can be used. While electrical cardioversion requires fasting and sedation of the patient, antiarrhythmic drugs have other limitations. Most antiarrhythmic drugs carry a risk for pro-arrhythmic effects and are contraindicated in patients with structural heart diseases. Furthermore, catheter ablation of pulmonary veins can be performed with its risk of intraprocedural complications and varying success. In recent years TASK-1 has been introduced as a new target for AF therapy. Upregulation of TASK-1 in AF patients contributes to prolongation of the action potential duration. In a porcine model of AF, TASK-1 inhibition by gene therapy or pharmacological compounds induced cardioversion to sinus rhythm. The DOxapram Conversion TO Sinus rhythm (DOCTOS)-Trial will reveal whether doxapram, a potent TASK-1 inhibitor, can be used for acute cardioversion of persistent and paroxysmal AF in patients, potentially leading to a new treatment option for AF.
PubMed: 33897427
DOI: 10.3389/fphar.2021.638445 -
Acta Physiologica (Oxford, England) Feb 2020The mode of action by which doxapram acts as a respiratory stimulant in humans is controversial. Studies in rodent models, have shown that doxapram is a more potent and...
AIMS
The mode of action by which doxapram acts as a respiratory stimulant in humans is controversial. Studies in rodent models, have shown that doxapram is a more potent and selective inhibitor of TASK-1 and TASK-1/TASK-3 heterodimer channels, than TASK-3. Here we investigate the direct effect of doxapram and chirally separated, individual positive and negative enantiomers of the compound, on both human and mouse, homodimeric and heterodimeric variants of TASK-1 and TASK-3.
METHODS
Whole-cell patch clamp electrophysiology on tsA201 cells was used to assess the potency of doxapram on cloned human or mouse TASK-1, TASK-3 and TASK-2 channels. Mutations of amino acids in the pore-lining region of TASK-3 channels were introduced using site-directed mutagenesis.
RESULTS
Doxapram was an equipotent inhibitor of human TASK-1 and TASK-3 channels, compared with mouse channel variants, where it was more selective for TASK-1 and heterodimers of TASK-1 and TASK-3. The effect of doxapram could be attenuated by either the removal of the C-terminus of human TASK-3 channels or mutations of particular hydrophobic residues in the pore-lining region. These mutations, however, did not alter the effect of a known extracellular inhibitor of TASK-3, zinc. The positive enantiomer of doxapram, GAL-054, was a more potent antagonist of TASK channels, than doxapram, whereas the negative enantiomer, GAL-053, had little inhibitory effect.
CONCLUSION
These data show that in contrast to rodent channels, doxapram is a potent inhibitor of both TASK-1 and TASK-3 human channels, providing further understanding of the pharmacological profile of doxapram in humans and informing the development of new therapeutic agents.
Topics: Cell Line; Doxapram; Humans; Nerve Tissue Proteins; Patch-Clamp Techniques; Potassium Channels, Tandem Pore Domain; Recombinant Proteins; Respiratory Insufficiency; Respiratory System Agents
PubMed: 31423744
DOI: 10.1111/apha.13361 -
Veterinary Medicine and Science Mar 2021The present prospective randomized experimental study was designed to determine the effects of doxapram on haematological, serum biochemical and antioxidant status in...
The present prospective randomized experimental study was designed to determine the effects of doxapram on haematological, serum biochemical and antioxidant status in dogs after propofol anaesthesia. Twenty-four healthy male mixed breed dogs, aged 1-2 years, weighing 20.4 ± 2.6 kg was studied. Each dog was anaesthetized twice, with at least one week for washout. Animals were sedated with acepromazine (0.1 mg/kg) intramuscularly. Forty minutes later, anaesthesia was induced using intravenous (IV) propofol (4 mg/kg) titration and maintained for 30 min by propofol (0.2 mg kg min ). After propofol was discontinued, doxapram (2 mg/kg) hydrochloride was administrated IV in PD treatment while an equal volume of saline was administrated in PS treatment. Blood parameters were analysed in four times: immediately before sedation (T1), after treatment (T2), after complete recovery (T3) and 24 hr later (T4). Haematological assessments revealed no significant difference between treatments except in haematocrit which was significantly reduced at T4 (24 hr later) in PD. A decreasing trend of all haematological variables was observed after doxapram administration until recovery, except monocyte, mean corpuscular haemoglobin, red blood cell distribution width and platelet count. Serum urea, creatinine, glucose, cholesterol, direct bilirubin concentration and alanine aminotransferase activity were not changed following doxapram administration compared to the PS treatment. After doxapram administration, Creatinine (T3), Albumin (T2) and Protein (T2 & T3) decreased while Glucose (T2 & T3) and BT (T3) increased. Antioxidant parameters measured showed no difference between treatments or time. Doxapram (2 mg/kg) IV did not induce any major negative effects on haematological, serum biochemical variables and oxidant/antioxidant status in dogs after propofol anaesthesia.
Topics: Anesthetics; Animals; Antioxidants; Blood Chemical Analysis; Central Nervous System Stimulants; Dogs; Doxapram; Erythrocytes; Hematologic Tests; Oxidants; Propofol
PubMed: 33210449
DOI: 10.1002/vms3.398 -
Frontiers in Pharmacology 2020Current drug dosing in preterm infants is standardized, mostly based on bodyweight. Still, covariates such as gestational and postnatal age may importantly alter...
INTRODUCTION
Current drug dosing in preterm infants is standardized, mostly based on bodyweight. Still, covariates such as gestational and postnatal age may importantly alter pharmacokinetics and pharmacodynamics. Evaluation of drug therapy in these patients is very difficult because objective pharmacodynamic parameters are generally lacking. By integrating continuous physiological data with model-based drug exposure and data on adverse drug reactions (ADRs), we aimed to show the potential benefit for optimized individual pharmacotherapy.
MATERIALS AND METHODS
Continuous data on oxygen saturation (SpO), fraction of inspired oxygen (FiO) and composite parameters, including the SpO/FiO ratio and the cumulative oxygen shortage under the 89% SpO limit, served as indicators for doxapram effectiveness. We analyzed these continuous effect data, integrated with doxapram exposure and ADR parameters, obtained in preterm infants around the start of doxapram therapy. The exposures to doxapram and the active metabolite keto-doxapram were simulated using a population pharmacokinetic model. Infants were selected and retrospectively compared on the indication to start doxapram, the first response to doxapram, a potential dose-response relationship, and the administered dosage over time. Recommendations were made for individual improvements of therapy.
RESULTS
We provide eight cases of continuous doxapram administration that illustrate a correct and incorrect indication to start doxapram, responders and non-responders to therapy, and unnecessary over-exposure with ADRs. Recommendations for improvement of therapy include: objective evaluation of added effect of doxapram after start, prevention of overdosing by earlier down-titration or termination of therapy, and the prevention of hypoxia and agitation by measuring specific parameters at strategical time-points.
CONCLUSION
Real-time and non-invasive effect monitoring of drug therapy combined with model-based exposure provides relevant information to clinicians and can importantly improve therapy. The variability between and within patients emphasizes the importance of individual, objective evaluation of pharmacotherapy. These measurements, together with data on ADRs, allow for precision medicine in neonatology that should be brought to the bedside.
PubMed: 32477133
DOI: 10.3389/fphar.2020.00665 -
Veterinary Surgery : VS Jan 2019To determine the influence of propofol or methohexital, with and without doxapram, on the examination of laryngeal function in dogs. (Comparative Study)
Comparative Study
OBJECTIVE
To determine the influence of propofol or methohexital, with and without doxapram, on the examination of laryngeal function in dogs.
STUDY DESIGN
Experimental study.
ANIMALS
Forty healthy dogs randomly assigned to 4 groups: propofol with saline (n = 10), propofol with doxapram (n = 10), methohexital with saline (n = 10), or methohexital with doxapram (n = 10).
METHODS
Propofol and methohexital were administered to effect. Investigators examined laryngeal function (initial) simultaneously with video laryngoscopy. Doxapram or saline was administered, and laryngeal function was reevaluated (second). Laryngeal motion, quality of laryngeal exposure, and the degree of swallowing, laryngospasm, and jaw tone were scored at each evaluation. Adverse events were recorded. Initial and second videos were evaluated by a masked observer, and still images obtained from both evaluations were evaluated for change in rima glottidis size by 2 masked observers.
RESULTS
Administration of doxapram and saline was delayed with propofol (P = .001). Laryngeal function did not differ between dogs receiving propofol or methohexital, irrespective of doxapram administration. Doxapram improved breathing scores in both groups (P < .001). Jaw tone increased with propofol during the second evaluation (P = .049). Swallowing was more prevalent at initial examination (P = .020). Methohexital resulted in an increased heart rate (P < .001) compared with propofol. Twenty-five percent of dogs receiving methohexital developed seizure-like activity (n = 5/20).
CONCLUSION
Evaluation of laryngeal function did not differ between healthy dogs anesthetized with propofol or methohexital. Methohexital provided shorter examination times with less jaw tone but was associated with adverse events.
CLINICAL SIGNIFICANCE
This study provides evidence to recommend propofol over methohexital as an induction agent for laryngeal function examination.
Topics: Anesthetics, Intravenous; Animals; Dogs; Doxapram; Female; Larynx; Male; Methohexital; Physical Examination; Propofol; Random Allocation; Respiratory System Agents; Treatment Outcome
PubMed: 30367699
DOI: 10.1111/vsu.13110 -
Neonatology 2020Evaluation of pharmacotherapy during intensive care treatment is commonly based on subjective, intermittent interpretations of physiological parameters. Real-time... (Observational Study)
Observational Study
INTRODUCTION
Evaluation of pharmacotherapy during intensive care treatment is commonly based on subjective, intermittent interpretations of physiological parameters. Real-time visualization and analysis may improve drug effect evaluation. We aimed to evaluate the effects of the respiratory stimulant doxapram objectively in preterm infants using continuous physiological parameters.
METHODS
In this longitudinal observational study, preterm infants who received doxapram therapy were eligible for inclusion. Physiological data (1 Hz) were used to assess respiration and to evaluate therapy effects. The oxygen saturation (SpO2)/fraction of inspired oxygen (FiO2) ratio and the area under the 89% SpO2 curve (duration × saturation depth below target) were calculated as measures of hypoxemia. Regression analyses were performed in 1-h timeframes to discriminate therapy failure (intubation or death) from success (no intubation).
RESULTS
Monitor data of 61 patients with a median postmenstrual age (PMA) at doxapram initiation of 28.7 (IQR 27.6-30.0) weeks were available. The success rate of doxapram therapy was 56%. Doxapram pharmacodynamics were reflected in an increased SpO2 and SpO2/FiO2 ratio as well as a decrease in episodes with saturations below target (SpO2 <89%). The SpO2/FiO2 ratio, corrected for PMA and mechanical ventilation before therapy start, discriminated best between therapy failure and success (highest AUC ROC of 0.83).
CONCLUSION
The use of continuous physiological monitor data enables objective and detailed interpretation of doxapram in preterm infants. The SpO2/FiO2 ratio is the best predictive parameter for therapy failure or success. Further implementation of real-time data analysis and treatment algorithms would provide new opportunities to treat newborns.
Topics: Doxapram; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Oxygen; Respiratory System Agents
PubMed: 32841955
DOI: 10.1159/000509269 -
Neonatology 2016Doxapram has been advocated as a treatment for persistent apnea of prematurity (AOP).
BACKGROUND
Doxapram has been advocated as a treatment for persistent apnea of prematurity (AOP).
OBJECTIVE
To evaluate the effect of doxapram on long-term neurodevelopmental outcome in preterm infants as its safety still needs to be established.
METHODS
From a retrospective cohort of preterm infants with a gestational age (GA) <30 weeks and/or a birth weight <1,250 g, born between 2000 and 2010, infants treated with doxapram (n = 142) and a nontreated control group were selected (n = 284). Patient characteristics and clinical and neurodevelopmental outcome data at 24 months' corrected age were collected. Neurodevelopmental delay (ND) was defined as having a Mental or Psychomotor Developmental Index (MDI/PDI) <-1 standard deviation (SD), cerebral palsy, or a hearing or visual impairment. Odds ratios (OR) were calculated using multiple logistic regression analyses adjusting for potential confounders.
RESULTS
Infants treated with doxapram had a lower GA compared to controls. The number of infants with a MDI or PDI <-1 SD was not different between the groups. The risk of the combined outcome death or ND was significantly lower in the doxapram group after adjusting for confounding factors (OR = 0.54, 95% CI: 0.37, 0.78). Doxapram-treated infants had a higher risk of bronchopulmonary dysplasia and patent ductus arteriosus, but a lower risk of spontaneous intestinal perforation. All other morbidities were not different between the groups.
CONCLUSIONS
This study suggests that doxapram is not associated with an increased risk of ND. These findings need to be confirmed or refuted by a large, well-designed, placebo-controlled randomized trial.
Topics: Apnea; Bronchopulmonary Dysplasia; Central Nervous System Stimulants; Child Development; Doxapram; Ductus Arteriosus, Patent; Female; Gestational Age; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Logistic Models; Male; Netherlands; Odds Ratio; Retrospective Studies; Treatment Outcome
PubMed: 26967910
DOI: 10.1159/000444006