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Cureus Jan 2022Premature babies often suffer apnea of prematurity as a physiological consequence of an immature respiratory system. Hypercapnia may develop, and neonates with apnea of... (Review)
Review
Premature babies often suffer apnea of prematurity as a physiological consequence of an immature respiratory system. Hypercapnia may develop, and neonates with apnea of prematurity are at an increased risk of morbidity and mortality. The long-term effects of apnea of prematurity or their treatments are less clear. While a number of treatment options exist for apnea of prematurity, there is no clear-cut "first-line" approach or gold standard of care. Effective treatments, such as caffeine citrate, carbon dioxide inhalation, nasal continuous positive airway pressure, nasal intermittent positive pressure ventilation, and others, may be associated with safety concerns. More conservative treatments are available, such as kangaroo care, postural changes, and sensory stimulation, but they may not be effective. While apnea of prematurity resolves spontaneously as the respiratory system matures, it can complicate neonatal care and may have both short-term and long-term consequences. The role, if any, that apnea of prematurity may play in mortality of preterm neonates is not clear.
PubMed: 35251853
DOI: 10.7759/cureus.21783 -
Pharmaceutics Mar 2022Atrial fibrillation (AF) is an arrhythmia associated with an increased stroke risk and mortality rate. Current treatment options leave unmet needs in AF therapy....
Atrial fibrillation (AF) is an arrhythmia associated with an increased stroke risk and mortality rate. Current treatment options leave unmet needs in AF therapy. Recently, doxapram has been introduced as a possible new option for AF treatment in a porcine animal model. To better understand its pharmacokinetics, three German Landrace pigs were treated with intravenous doxapram (1 mg/kg). Plasma and brain tissue samples were collected. For the analysis of these samples, an ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay for the simultaneous measurement of doxapram and its active metabolite 2-ketodoxapram was developed and validated. The assay had a lower limit of quantification (LLOQ) of 10 pg/mL for plasma and 1 pg/sample for brain tissue. In pigs, doxapram pharmacokinetics were biphasic with a terminal elimination half-life (t) of 1.38 ± 0.22 h and a maximal plasma concentration (c) of 1780 ± 275 ng/mL. Its active metabolite 2-ketodoxapram had a t of 2.42 ± 0.04 h and c of 32.3 ± 5.5 h after administration of doxapram. Protein binding was 95.5 ± 0.9% for doxapram and 98.4 ± 0.3% for 2-ketodoxapram with a brain-to-plasma ratio of 0.58 ± 0.24 for doxapram and 0.12 ± 0.02 for 2-ketodoxapram. In conclusion, the developed assay was successfully applied to the creation of pharmacokinetic data for doxapram, possibly improving the safety of its usage.
PubMed: 35456597
DOI: 10.3390/pharmaceutics14040762 -
American Journal of Veterinary Research Jan 2021To determine the effects of dexmedetomidine, doxapram, and dexmedetomidine plus doxapram on ventilation ([Formula: see text]e), breath frequency, and tidal volume (Vt)...
OBJECTIVE
To determine the effects of dexmedetomidine, doxapram, and dexmedetomidine plus doxapram on ventilation ([Formula: see text]e), breath frequency, and tidal volume (Vt) in ball pythons () and of doxapram on the thermal antinociceptive efficacy of dexmedetomidine.
ANIMALS
14 ball pythons.
PROCEDURES
Respiratory effects of dexmedetomidine and doxapram were assessed with whole-body, closed-chamber plethysmography, which allowed for estimates of [Formula: see text]e and Vt. In the first experiment of this study with a complete crossover design, snakes were injected, SC, with saline (0.9% NaCl) solution, dexmedetomidine (0.1 mg/kg), doxapram (10 mg/kg), or dexmedetomidine and doxapram, and breath frequency, [Formula: see text]e, and Vt were measured before and every 30 minutes thereafter, through 240 minutes. In the second experiment, antinociceptive efficacy of saline solution, dexmedetomidine, and dexmedetomidine plus doxapram was assessed by measuring thermal withdrawal latencies before and 60 minutes after SC injection.
RESULTS
Dexmedetomidine significantly decreased breath frequency and increased Vt but did not affect [Formula: see text]e at all time points, compared with baseline. Doxapram significantly increased [Formula: see text]e, breath frequency, and Vt at 60 minutes after injection, compared with saline solution. The combination of dexmedetomidine and doxapram, compared with dexmedetomidine alone, significantly increased [Formula: see text]e at 30 and 60 minutes after injection and did not affect breath frequency and Vt at all time points. Thermal withdrawal latencies significantly increased when snakes received dexmedetomidine or dexmedetomidine plus doxapram, versus saline solution.
CONCLUSIONS AND CLINICAL RELEVANCE
Concurrent administration of doxapram may mitigate the dexmedetomidine-induced reduction of breathing frequency without disrupting thermal antinociceptive efficacy in ball pythons.
Topics: Analgesics; Animals; Boidae; Dexmedetomidine; Doxapram; Respiration
PubMed: 33369496
DOI: 10.2460/ajvr.82.1.11 -
Animals : An Open Access Journal From... Mar 2020Anaesthetic drugs are commonly used during the evaluation of laryngeal function in dogs. The aim of this review was to systematically analyse the literature describing... (Review)
Review
Anaesthetic drugs are commonly used during the evaluation of laryngeal function in dogs. The aim of this review was to systematically analyse the literature describing the effects of anaesthetic drugs and doxapram on laryngeal motion in dogs and to determine which drug regime provides the best conditions for laryngeal examination. PubMed, Google Scholar, and EMBASE databases were used for the literature search up to November 2019. Relevant search terms included laryngeal motion, anaesthetic drugs and dogs. Studies were scored based on their level of evidence (LoE), according to the Oxford Centre for Evidence-based Medicine, and the quality was assessed using the risk-of-bias tool and SIGN-checklist. In healthy dogs, premedication before laryngeal examination provided better examination conditions and maintained overall adequate laryngeal motion in 83% of the studies. No difference in laryngeal motion between induction drugs was found in 73% of the studies but the effects in dogs with laryngeal paralysis remain largely unknown. Doxapram increased laryngeal motion in healthy dogs without serious side effects, but intubation was necessary for some dogs with laryngeal paralysis. Methodological characteristics varied considerably between studies, including the technique and timing of evaluation, number of assessors, study design, drug dose, combinations, route and speed of administration.
PubMed: 32235700
DOI: 10.3390/ani10030530 -
Children (Basel, Switzerland) Nov 2022QTc interval measurement is a widely used screening tool to assess the risk of cardiac diseases, arrhythmias, and is a useful biomarker for pharmacovigilance. However,... (Review)
Review
QTc interval measurement is a widely used screening tool to assess the risk of cardiac diseases, arrhythmias, and is a useful biomarker for pharmacovigilance. However, the interpretation of QTc is difficult in neonates due to hemodynamic maturational changes and uncertainties on reference values. To describe trends in QTc values throughout infancy (1 year of life), and to explore the impact of (non)-maturational changes and medicines exposure, a structured systematic review (PROSPERO CRD42022302296) was performed. In term neonates, a decrease was observed over the first week of life, whereafter values increased until two months of age, followed by a progressive decrease until six months. A similar pattern with longer QTc values was observed in preterms. QTc is influenced by cord clamping, hemodynamic changes, therapeutic hypothermia, illnesses and sleep, not by sex. Cisapride, domperidone and doxapram result in QTc prolongation in neonates. Further research in this age category is needed to improve primary screening practices and QTcthresholds, earlier detection of risk factors and precision pharmacovigilance.
PubMed: 36421220
DOI: 10.3390/children9111771 -
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 -
Neonatology 2021Apnea of prematurity can persist despite caffeine therapy in preterm infants. Doxapram may additionally support breathing. Although multiple small studies have reported...
BACKGROUND
Apnea of prematurity can persist despite caffeine therapy in preterm infants. Doxapram may additionally support breathing. Although multiple small studies have reported the efficacy of doxapram, the structural co-treatment with caffeine impedes to ascribe the efficacy to doxapram itself or to a pharmacokinetic (PK) interaction where doxapram increases the exposure to caffeine. We examined whether there is a PK drug-drug interaction between doxapram and caffeine by developing a PK model for caffeine including infants with and without doxapram treatment.
METHODS
In preterm neonates receiving caffeine, we determined caffeine plasma concentrations before, during, and directly after doxapram co-treatment and used these to develop a population PK model in NONMEM 7.3. Patient characteristics and concomitant doxapram administration were tested as covariates.
RESULTS
166 plasma samples were collected from 39 preterm neonates receiving caffeine (median gestational age 25.6 [range 24.0-28.0] weeks) of which 65 samples were taken during co-treatment with doxapram (39%, from 32/39 infants). Clearance of caffeine was 9.99 mL/h for a typical preterm neonate with a birth weight of 0.8 kg and 23 days postnatal age and increased with birth weight and postnatal age, resulting in a 4-fold increase in clearance during the first month of life. No PK interaction between caffeine and doxapram was identified.
DISCUSSION
Caffeine clearance is not affected by concomitant doxapram therapy but shows a rapid maturation with postnatal age. As current guidelines do not adjust the caffeine dose with postnatal age, decreased exposure to caffeine might partly explain the need for doxapram therapy after the first week of life.
Topics: Apnea; Caffeine; Doxapram; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases
PubMed: 33626528
DOI: 10.1159/000513413 -
MBio Mar 2020Frequent and excessive use of antibiotics primes patients to infection (CDI), which leads to fatal pseudomembranous colitis, with limited treatment options. In earlier...
Frequent and excessive use of antibiotics primes patients to infection (CDI), which leads to fatal pseudomembranous colitis, with limited treatment options. In earlier reports, we used a drug repurposing strategy and identified amoxapine (an antidepressant), doxapram (a breathing stimulant), and trifluoperazine (an antipsychotic), which provided significant protection to mice against lethal infections with several pathogens, including However, the mechanisms of action of these drugs were not known. Here, we provide evidence that all three drugs offered protection against experimental CDI by reducing bacterial burden and toxin levels, although the drugs were neither bacteriostatic nor bactericidal in nature and had minimal impact on the composition of the microbiota. Drug-mediated protection was dependent on the presence of the microbiota, implicating its role in evoking host defenses that promoted protective immunity. By utilizing transcriptome sequencing (RNA-seq), we identified that each drug increased expression of several innate immune response-related genes, including those involved in the recruitment of neutrophils, the production of interleukin 33 (IL-33), and the IL-22 signaling pathway. The RNA-seq data on selected genes were confirmed by quantitative real-time PCR (qRT-PCR) and protein assays. Focusing on amoxapine, which had the best anti-CDI outcome, we demonstrated that neutralization of IL-33 or depletion of neutrophils resulted in loss of drug efficacy. Overall, our lead drugs promote disease alleviation and survival in the murine model through activation of IL-33 and by clearing the pathogen through host defense mechanisms that critically include an early influx of neutrophils. is a spore-forming anaerobic bacterium and the leading cause of antibiotic-associated colitis. With few therapeutic options and high rates of disease recurrence, the need to develop new treatment options is urgent. Prior studies utilizing a repurposing approach identified three nonantibiotic Food and Drug Administration-approved drugs, amoxapine, doxapram, and trifluoperazine, with efficacy against a broad range of human pathogens; however, the protective mechanisms remained unknown. Here, we identified mechanisms leading to drug efficacy in a murine model of lethal infection (CDI), advancing our understanding of the role of these drugs in infectious disease pathogenesis that center on host immune responses to Overall, these studies highlight the crucial involvement of innate immune responses, as well as the importance of immunomodulation as a potential therapeutic option to combat CDI.
Topics: Amoxapine; Animals; Clostridioides difficile; Clostridium Infections; Doxapram; Drug Repositioning; Female; Immunity, Innate; Immunomodulation; Male; Mice; Mice, Inbred C57BL; Microbiota; RNA-Seq; Specific Pathogen-Free Organisms; Trifluoperazine
PubMed: 32156806
DOI: 10.1128/mBio.00053-20 -
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 Apr 2022Opioids may produce life-threatening respiratory depression and death from their actions at the opioid receptors within the brainstem respiratory neuronal network. Since...
Opioids may produce life-threatening respiratory depression and death from their actions at the opioid receptors within the brainstem respiratory neuronal network. Since there is an increasing number of conditions where the administration of the opioid receptor antagonist naloxone is inadequate or undesired, there is an increased interest in the development of novel reversal and prevention strategies aimed at providing efficacy close to that of the opioid receptor antagonist naloxone but with fewer of its drawbacks such as its short duration of action and lesser ability to reverse high-affinity opioids, such as carfentanil, or drug combinations. To give an overview of this highly relevant topic, the authors systematically discuss predominantly experimental pharmacotherapies, published in the last 5 yr, aimed at reversal of opioid-induced respiratory depression as alternatives to naloxone. The respiratory stimulants are discussed based on their characteristics and mechanism of action: nonopioid controlled substances (e.g., amphetamine, cannabinoids, ketamine), hormones (thyrotropin releasing hormone, oxytocin), nicotinic acetylcholine receptor agonists, ampakines, serotonin receptor agonists, antioxidants, miscellaneous peptides, potassium channel blockers acting at the carotid bodies (doxapram, ENA001), sequestration techniques (scrubber molecules, immunopharmacotherapy), and opioids (partial agonists/antagonists). The authors argue that none of these often still experimental therapies are sufficiently tested with respect to efficacy and safety, and many of the agents presented have a lesser efficacy at deeper levels of respiratory depression, i.e., inability to overcome apnea, or have ample side effects. The authors suggest development of reversal strategies that combine respiratory stimulants with naloxone. Furthermore, they encourage collaborations between research groups to expedite development of viable reversal strategies of potent synthetic opioid-induced respiratory depression.
Topics: Analgesics, Opioid; Humans; Naloxone; Narcotic Antagonists; Respiratory Insufficiency; Respiratory System Agents
PubMed: 34958670
DOI: 10.1097/ALN.0000000000004096