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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 -
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 -
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 -
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 -
Surgical Endoscopy Dec 2020Endoscopic retrograde cholangiopancreatography (ERCP) requires moderate to deep sedation, usually with propofol. Adverse effects of propofol sedation are relatively... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Endoscopic retrograde cholangiopancreatography (ERCP) requires moderate to deep sedation, usually with propofol. Adverse effects of propofol sedation are relatively common, such as respiratory and cardiovascular depression. This study was conducted to determine if doxapram, a respiratory stimulant, could be used to reduce the incidence of respiratory depression.
METHODS
This is a single-center, prospective randomized double-blind study performed in the endoscopy unit of Helsinki University Central Hospital. 56 patients were randomized in a 1:1 ratio to either receive doxapram as an initial 1 mg/kg bolus and an infusion of 1 mg/kg/h (group DOX) or placebo (group P) during propofol sedation for ERCP. Main outcome measures were apneic episodes and hypoxemia (SpO < 90%). Mann-Whitney test for continuous variables and Fisher's exact test for discrete variables were used and mixed effects modeling to take into account repeated measurements on the same subject and comparing both changes within a group as a function of time and between the groups.
RESULTS
There were no statistically significant differences in apneic episodes (p = 0.18) or hypoxemia (p = 0.53) between the groups. There was a statistically significant rise in etCO levels in both groups, but the rise was smaller in group P. There was a statistically significant rise in Bispectral Index (p = 0.002) but not modified Observer's Assessment of Agitation/Sedation (p = 0.21) in group P. There were no statistically significant differences in any other measured parameters.
CONCLUSIONS
Doxapram was not effective in reducing respiratory depression caused by deep propofol sedation during ERCP. Further studies are warranted using different sedation protocols and dosing regimens. Clinical trial registration ClinicalTrials.gov ID NCT02171910.
Topics: Adult; Aged; Cholangiopancreatography, Endoscopic Retrograde; Double-Blind Method; Doxapram; Female; Humans; Hypnotics and Sedatives; Male; Middle Aged; Propofol; Prospective Studies; Young Adult
PubMed: 31993819
DOI: 10.1007/s00464-019-07344-2 -
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 -
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 -
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 -
British Journal of Anaesthesia Jun 2019Opioids are potent painkillers but come with serious adverse effects ranging from addiction to potentially lethal respiratory depression. A variety of drugs with... (Review)
Review
BACKGROUND
Opioids are potent painkillers but come with serious adverse effects ranging from addiction to potentially lethal respiratory depression. A variety of drugs with separate mechanisms of action are available to prevent or reverse opioid-induced respiratory depression (OIRD).
METHODS
The authors reviewed human studies on reversal of OIRD using models that describe and predict the time course of pharmacokinetics (PK) and pharmacodynamics (PD) of opioids and reversal agents and link PK to PD.
RESULTS
The PKPD models differ in their basic structure to capture the specific pharmacological mechanisms by which reversal agents interact with opioid effects on breathing. The effect of naloxone, a competitive opioid receptor antagonist, is described by the combined effect-compartment receptor-binding model to quantify rate limitation at the level of drug distribution and receptor kinetics. The effects of reversal agents that act through non-opioidergic pathways, such as ketamine and the experimental drug GAL021, are described by physiological models, in which stimulants act at CO chemosensitivity, CO-independent ventilation, or both. The PKPD analyses show that although all reversal strategies may be effective under certain circumstances, there are conditions at which reversal is less efficacious and sometimes even impossible.
CONCLUSIONS
Model-based drug development is needed to design an 'ideal' reversal agent-that is, one that is not influenced by opioid receptor kinetics, does not interfere with opioid analgesia, has a rapid onset of action with long-lasting effects, and is devoid of adverse effects.
Topics: Analgesics, Opioid; Carotid Body; Doxapram; Drug Design; Humans; Models, Biological; Naloxone; Narcotic Antagonists; Respiratory Insufficiency; Triazines
PubMed: 30915997
DOI: 10.1016/j.bja.2018.12.023 -
Journal of Neurophysiology Apr 2019Doxapram is a respiratory stimulant used for decades as a treatment option in apnea of prematurity refractory to methylxanthine treatment. Its mode of action, however,...
Doxapram is a respiratory stimulant used for decades as a treatment option in apnea of prematurity refractory to methylxanthine treatment. Its mode of action, however, is still poorly understood. We investigated direct effects of doxapram on the pre-Bötzinger complex (PreBötC) and on a downstream motor output system, the hypoglossal nucleus (XII), in the transverse brainstem slice preparation. While doxapram has only a modest stimulatory effect on frequency of activity generated within the PreBötC, a much more robust increase in the amplitude of population activity in the subsequent motor output generated in the XII was observed. In whole cell patch-clamp recordings of PreBötC and XII neurons, we confirmed significantly increased firing of evoked action potentials in XII neurons in the presence of doxapram, while PreBötC neurons showed no significant alteration in firing properties. Interestingly, the amplitude of activity in the motor output was not increased in the presence of doxapram compared with control conditions during hypoxia. We conclude that part of the stimulatory effects of doxapram is caused by direct input on brainstem centers with differential effects on the rhythm generating kernel (PreBötC) and the downstream motor output (XII). NEW & NOTEWORTHY The clinically used respiratory stimulant doxapram has distinct effects on the rhythm generating kernel (pre-Bötzinger complex) and motor output centers (nucleus hypoglossus). These effects are obliterated during hypoxia and are mediated by distinct changes in the intrinsic properties of neurons of the nucleus hypoglossus and synaptic transmission received by pre-Bötzinger complex neurons.
Topics: Action Potentials; Animals; Brain Stem; Central Nervous System Stimulants; Central Pattern Generators; Doxapram; Female; Hypoglossal Nerve; Male; Mice; Motor Neurons; Respiration; Respiratory System Agents
PubMed: 30699003
DOI: 10.1152/jn.00304.2018