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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 -
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 -
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 -
JAMA Pediatrics Feb 2017Clinicians aim to extubate preterm infants as early as possible, to minimize the risks of mechanical ventilation. Extubation is often unsuccessful owing to lung disease... (Meta-Analysis)
Meta-Analysis Review
IMPORTANCE
Clinicians aim to extubate preterm infants as early as possible, to minimize the risks of mechanical ventilation. Extubation is often unsuccessful owing to lung disease or inadequate respiratory drive.
OBJECTIVE
To conduct a systematic review and meta-analysis of interventions to improve rates of successful extubation in preterm infants.
DATA SOURCES
Searches were undertaken in PubMed and The Cochrane Library.
STUDY SELECTION
The review was conducted using the methods of the Cochrane Collaboration and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies were included if they were randomized clinical trials published in English, enrolled intubated preterm infants (born <37 weeks' gestation), and reported 1 or both of the primary outcomes.
DATA EXTRACTION AND SYNTHESIS
One thousand three hundred seventy-nine titles were screened independently by 2 investigators to assess need for full-text review. Disagreements were resolved via consensus of all authors. Where no Cochrane Review existed for an intervention, or not all identified studies were included, a new pooled analysis was performed.
MAIN OUTCOMES AND MEASURES
Primary outcomes were treatment failure or reintubation within 7 days of extubation.
RESULTS
Fifty studies were eligible for inclusion. Continuous positive airway pressure reduced extubation failure in comparison with head-box oxygen (risk ratio [RR], 0.59; 95% CI, 0.48-0.72; number needed to treat [NNT], 6; 95% CI, 3-9). Nasal intermittent positive pressure ventilation was superior to continuous positive airway pressure in preventing extubation failure (RR, 0.70; 95% CI, 0.60-0.81; NNT, 8; 95% CI, 5-13). High-flow nasal cannula therapy and continuous positive airway pressure had similar efficacy (RR, 1.11; 95% CI, 0.84-1.47). Methylxanthines reduced extubation failure (RR, 0.48; 95% CI, 0.32-0.71; NNT, 4; 95% CI, 2-7) compared with placebo or no treatment. Corticosteroids (RR, 0.18; 95% CI, 0.04-0.97; NNT, 12; 95% CI, 6-100) and chest physiotherapy (RR, 0.32; 95% CI, 0.13-0.82; NNT, 15; 95% CI, 7-50) both reduced extubation failure rates but were associated with significant adverse effects. Doxapram did not aid successful extubation (RR, 0.80; 95% CI, 0.22-2.97).
CONCLUSIONS AND RELEVANCE
Preterm infants should be extubated to noninvasive respiratory support. Caffeine should be used routinely, while corticosteroids should be used judiciously, weighing up the competing risks of bronchopulmonary dysplasia and neurodevelopmental harm.
Topics: Airway Extubation; Evidence-Based Medicine; Humans; Infant, Newborn; Infant, Premature; Quality Improvement
PubMed: 27918754
DOI: 10.1001/jamapediatrics.2016.3015 -
European Journal of Pediatrics Apr 2015This study aimed to determine the population pharmacokinetics of doxapram in low-birth-weight (LBW) infants. A total of 92 serum concentration measurements that were... (Randomized Controlled Trial)
Randomized Controlled Trial
UNLABELLED
This study aimed to determine the population pharmacokinetics of doxapram in low-birth-weight (LBW) infants. A total of 92 serum concentration measurements that were obtained from 34 Japanese neonates were analyzed using nonlinear mixed-effect modeling (NONMEM). Estimates generated by NONMEM indicated that clearance of doxapram (CL; L/kg/h) was affected by postmenstrual age (PMA; weeks), body weight (BW; g), and aspartate aminotransferase (AST; IU/L). In addition, the volume of distribution (Vd; L/kg) was affected by gestational age (GA; weeks). The final pharmacokinetic model was as follows: CL = BW / PMA × 0.0453 × serum AST(-0.373); Vd = 2.54 (if GA >28 weeks) and Vd = 2.54 × 2.11 (if GA ≤28 weeks). The interindividual variabilities in CL and Vd were 39.9 and 83.0 %, respectively, and the residual variability was 20.9 %. To clarify the reasons for large interindividual variations, the enzymes involved in the metabolic pathway of doxapram were also determined. We found that doxapram was metabolized by CYP3A4/5.
CONCLUSION
We report the population pharmacokinetics of doxapram in neonates and the involvement of CYP3A4/5 in its metabolism. The final model of population pharmacokinetics may be useful for formulating a safe and effective dosage regimen and for predicting serum doxapram concentrations in neonates.
Topics: Apnea; Asian People; Central Nervous System Stimulants; Chromatography, High Pressure Liquid; Cytochrome P-450 Enzyme System; Double-Blind Method; Doxapram; Female; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Japan; Male; Mass Spectrometry; Models, Biological
PubMed: 25248340
DOI: 10.1007/s00431-014-2416-1 -
Paediatric Drugs Dec 2016Doxapram is used as a third-line treatment for apnea unresponsive to caffeine and continuous positive airway pressure (CPAP) in preterm infants. (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Doxapram is used as a third-line treatment for apnea unresponsive to caffeine and continuous positive airway pressure (CPAP) in preterm infants.
OBJECTIVES
The objectives of this study were to compare the effects of dosing adjusted for gender and postmenstrual age (PMA) (GrA) versus infants' weight alone (GrW) on doxapram plasma levels, clinical efficacy, and side effects.
METHODS
This was a randomized, double-blind study, including premature infants for whom optimized caffeine and CPAP therapy for apnea of prematurity had failed. Failure was defined as the persistence of more than one significant apnea per hour over an 8-h period. Plasma levels of doxapram and ketodoxapram were measured with high-performance liquid chromatography (HPLC) 48 h after the onset of treatment. Dosing aimed to maintain the combined doxapram and ketodoxapram plasma level in the therapeutic range of 1.5-4 mg/l. Infants were followed-up for 4 days after the onset of treatment.
RESULTS
A total of 85 infants were included: 46 in GrW (27.7 ± 1.9 weeks' gestational age [GA]), 39 in GrA (27.9 ± 1.4 weeks' GA); available plasma levels showed that 25 of 40 in the GrW group and 27 of 37 in the GrA group had levels within the therapeutic range (p = 0.344). Of note, plasma level variance was significantly higher in GrW for doxapram + ketodoxapram (1.87 vs. 0.89; p = 0.028). Clinical efficacy was better in the GrA group, with a reduction from 32 to 3 of 38 (76 %) infants with significant apnea versus 30 to 5 of 45 (56 %) in the GrW group (p < 0.001). No adverse effects were observed during the study.
CONCLUSIONS
Taking gender and PMA into account for doxapram dosing did not significantly increase the number of infants with a plasma level in the therapeutic range. However, it improved plasma level stability and clinical efficacy without adverse effects. ClinicalTrials.gov number: NCT00389909.
Topics: Apnea; Double-Blind Method; Doxapram; Female; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Male; Prospective Studies; Respiratory System Agents
PubMed: 27612991
DOI: 10.1007/s40272-016-0192-2 -
Comparative Biochemistry and... Apr 2023Exposure of Drosophila skeletal muscle to bacterial lipopolysaccharides (LPS) rapidly and transiently hyperpolarizes membrane potential. However, the mechanism...
Exposure of Drosophila skeletal muscle to bacterial lipopolysaccharides (LPS) rapidly and transiently hyperpolarizes membrane potential. However, the mechanism responsible for hyperpolarization remains unclear. The resting membrane potential of the cells is maintained through multiple mechanisms. This study investigated the possibility of LPS activating calcium-activated potassium channels (K) and/or K2p channels. 2-Aminoethyl diphenylborinate (2-APB), blocks uptake of Ca into the endoplasmic reticulum (ER); thus, limiting release from ryanodine-sensitive internal stores to reduce the function of K channels. Exposure to 2-APB produces waves of hyperpolarization even during desensitization of the response to LPS and in the presence of doxapram. This finding in this study suggests that doxapram blocked the acid-sensitive K2p tandem-pore channel subtype known in mammals. Doxapram blocked LPS-induced hyperpolarization and depolarized the muscles as well as induced motor neurons to produce evoked excitatory junction potentials (EJPs). This was induced by depolarizing motor neurons, similar to the increase in extracellular K concentration. The hyperpolarizing effect of LPS was not blocked by decreased extracellular Caor the presence of Cd. LPS appears to transiently activate doxapram sensitive K2p channels independently of K channels in hyperpolarizing the muscle. Septicemia induced by gram-negative bacteria results in an increase in inflammatory cytokines, primarily induced by bacterial LPS. Currently, blockers of LPS receptors in mammals are unknown; further research on doxapram and other K2p channels is warranted. (220 words).
Topics: Animals; Doxapram; Membrane Potentials; Potassium Channels, Tandem Pore Domain; Lipopolysaccharides; Ryanodine; Mammals
PubMed: 36740004
DOI: 10.1016/j.cbpc.2023.109571 -
Veterinary Surgery : VS Jan 2020To determine the ability to evaluate laryngeal function under sedation with dexmedetomidine alone or in combination with opioids.
OBJECTIVE
To determine the ability to evaluate laryngeal function under sedation with dexmedetomidine alone or in combination with opioids.
STUDY DESIGN
Randomized, crossover, blinded study.
ANIMALS
Eight adult research hounds weighing 8 to 22.5 kg.
METHODS
Dogs were sedated with propofol, dexmedetomidine, dexmedetomidine and butorphanol, or dexmedetomidine and hydromorphone. Digital images were collected with video laryngoscopy before and after doxapram administration. Maximal inspiratory normalized glottal gap (GGA ) and laryngeal motion were compared between and within protocols before and after doxapram by using a difference of least squares mean.
RESULTS
Normal laryngeal function was confirmed in all dogs with all protocols except propofol, which resulted in two false positive results. No difference between protocols was detected for predoxapram GGA . Postdoxapram GGA was greater than predoxapram GGA for all four sedation protocols (P ≤ .0030). Compared with propofol, postdoxapram GGA was greater for all three dexmedetomidine protocols (P ≤ .0420).
CONCLUSION
Dexmedetomidine alone or in combination with opioids was an effective sedation protocol for laryngeal examination, producing sufficient immobilization to prevent jaw motion and without affecting arytenoid abduction.
CLINICAL SIGNIFICANCE
Dexmedetomidine sedation does not inhibit normal laryngeal motion. Laryngeal examination with propofol alone can produce false positive results.
Topics: Analgesics, Opioid; Animals; Butorphanol; Conscious Sedation; Cross-Over Studies; Dexmedetomidine; Dogs; Hydromorphone; Hypnotics and Sedatives; Larynx; Random Allocation
PubMed: 31603562
DOI: 10.1111/vsu.13334