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British Journal of Anaesthesia Jun 1989We have studied the action of doxapram on neuromuscular transmission in the rat phrenic nerve-diaphragm preparation. Doxapram augmented neuromuscular transmission in a...
We have studied the action of doxapram on neuromuscular transmission in the rat phrenic nerve-diaphragm preparation. Doxapram augmented neuromuscular transmission in a dose-related manner when a threshold concentration of 5 x 10(-5) mol litre-1 had been exceeded. The activity of the acetylcholinesterase in rat diaphragm has been examined also in the presence of doxapram. No inhibitory effect was seen in the concentration range which augmented neuromuscular transmission, thus excluding cholinesterase inhibition as the underlying mechanism. In contrast, in the presence of partial neuromuscular block, a dose-related depression of neuromuscular transmission with doxapram was revealed. This was greatest when the neuromuscular blocking agents possessed significant presynaptic activity (beta-bungarotoxin and tubocurarine). In this situation any facilitatory action of doxapram was severely reduced or abolished. In contrast, the facilitatory effects of doxapram were apparent in the presence of partial block produced by agents with less or no presynaptic activity (pancuronium and alpha-bungarotoxin). This study suggests that doxapram has a presynaptic facilitatory action at the neuromuscular junction. In the presence of partial neuromuscular block, an inhibitory action is revealed which may be post-junctional. The concentrations of doxapram at which these effects appear are approximately five times greater than those reached in plasma after a standard clinical dose.
Topics: Acetylcholinesterase; Animals; Diaphragm; Dose-Response Relationship, Drug; Doxapram; Male; Muscle Contraction; Neuromuscular Blocking Agents; Neuromuscular Junction; Phrenic Nerve; Rats; Rats, Inbred Strains
PubMed: 2751921
DOI: 10.1093/bja/62.6.664 -
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 -
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 -
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 -
Anaesthesia Mar 1982In a double-blind trial the effects of a single dose of doxapram (1--1.5 mg/kg) on the postoperative arterial oxygen tension of patients who had undergone surgical... (Clinical Trial)
Clinical Trial
In a double-blind trial the effects of a single dose of doxapram (1--1.5 mg/kg) on the postoperative arterial oxygen tension of patients who had undergone surgical fixation of a fractured neck of femur was measured. In contrast to other reports of the effect of a single dose of doxapram, there was no improvement in arterial oxygen tension with respect to the control group. It is reasoned that doxapram may exert its effect by increasing the functional residual capacity in the immediate postoperative period. The central analeptic properties of doxapram may be grossly underestimated. The widely held assumption that patients with a fractured neck of femur are significantly hypoxic pre-operatively is questioned.
Topics: Aged; Carbon Dioxide; Clinical Trials as Topic; Double-Blind Method; Doxapram; Femoral Neck Fractures; Humans; Hypoxia; Middle Aged; Oxygen; Partial Pressure; Postoperative Complications
PubMed: 6807125
DOI: 10.1111/j.1365-2044.1982.tb01103.x -
Journal of Perinatology : Official... Jun 2018We often encounter infants who developed hypokalaemia following low-dose doxapram for apnea of prematurity (AOP).
OBJECTIVE
We often encounter infants who developed hypokalaemia following low-dose doxapram for apnea of prematurity (AOP).
AIMS
To determine changes in blood potassium (K+) levels after doxapram administration.
STUDY DESIGN
We studied infants born before 30 weeks gestation. Doxapram (0.1-0.3 mg/kg/h) in addition to methylxanthines was used to treat AOP refractory to methylxanthines.
RESULTS
Twenty-five infants received doxapram were studied. Fifty-two percent developed hypokalemia (<3.0 mEq/L) during doxapram administration. Time after starting doxapram to nadir blood K+ (<3.0 mEq/L) level was 11 days. Blood K+ levels normalized after 5 days of stopping doxapram administration. Data at 10 days before and after and at the time of doxapram administration were, respectively: lowest blood K+ level: 3.9, 3.0, and 3.6 mEq/L; urine aldosterone: 90, 206, and 146 pg/μg creatinine. Blood pH, blood pressure and urine volume were similar.
CONCLUSIONS
Doxapram-induced hypokalemia may be due to an inappropriate increase in aldosterone levels.
Topics: Aldosterone; Cohort Studies; Creatinine; Dose-Response Relationship, Drug; Doxapram; Drug Administration Schedule; Female; Follow-Up Studies; Gestational Age; Hospitals, Pediatric; Humans; Hypokalemia; Incidence; Infant, Newborn; Infant, Premature; Japan; Male; Respiratory Distress Syndrome, Newborn; Retrospective Studies; Risk Assessment; Severity of Illness Index; Xanthines
PubMed: 29515224
DOI: 10.1038/s41372-018-0087-x -
Anaesthesia Jan 1990
Topics: Analgesia, Epidural; Doxapram; Humans; Middle Aged; Morphine; Respiratory Insufficiency
PubMed: 2316851
DOI: 10.1111/j.1365-2044.1990.tb14524.x -
Equine Veterinary Journal. Supplement Feb 1992The pharmacokinetics and metabolism of doxapram in horses administered intravenous (iv) doses of 0.275, 0.55 and 1.1 mg doxapram/kg bodyweight (bwt) were investigated....
The pharmacokinetics and metabolism of doxapram in horses administered intravenous (iv) doses of 0.275, 0.55 and 1.1 mg doxapram/kg bodyweight (bwt) were investigated. Plasma doxapram concentrations decreased rapidly after drug administration and the disappearance of doxapram from plasma was best described by a polyexponential equation. Median values of total body clearance were 10.9, 10.6 and 10.9 ml/min/kg bwt for the three doses and were independent of dose. The steady-state volume of distribution was approximately 1,200 ml/kg bwt and the median biological half-life ranged from 121 to 178 mins. Plasma protein binding of doxapram ranged from 76.0 to 85.4 per cent. The blood:plasma doxapram concentration ratio was approximately 0.8 and the affinity of the red blood cells for doxapram ranged from 2.0 to 2.8 indicating sequestration of doxapram in erythrocytes. Renal clearance of doxapram was a minor route of elimination. Metabolic clearance of doxapram appeared to be a major route of elimination. Four metabolites of doxapram were isolated from urine and were identified. The metabolites were: a) 1-ethyl-4-[(2-hydroxyethyl) amino]ethyl-3,3-diphenyl-2-pyr-rolidinone, b) a glucuronic acid or sulphuric acid conjugate of 1-ethyl-3-(hydroxyphenyl)-4-(2-morpholinoethyl)-3-phenyl-pyrrolidinone, c) 3,3-diphenyl-4-(2-morpholinoethyl)-2-pyrrolidinone and d) 1-(2-hydroxyethyl)-3,3-diphenyl-4-(2-morpholinoethyl)-2-pyr-rolidinon e. The rapid disappearance of doxapram from plasma immediately after iv administration was attributed to redistribution of the drug from plasma to other tissues. The short duration of clinical effect from doxapram may be attributed to redistribution of the drug from plasma and other well-perfused tissues, such as the brain, to less well-perfused tissues such as the skeletal muscles and adipose tissue. Continuous or repeated administration of doxapram could prolong the duration of clinical effect because re-distribution is less important as steady-state conditions are approached.
Topics: Adipose Tissue; Animals; Blood Proteins; Brain; Central Nervous System Stimulants; Dose-Response Relationship, Drug; Doxapram; Erythrocytes; Female; Half-Life; Horses; Injections, Intravenous; Male; Muscle, Skeletal; Protein Binding; Tissue Distribution
PubMed: 9109960
DOI: 10.1111/j.2042-3306.1992.tb04772.x -
Developmental Pharmacology and... 1988Pharmacokinetics of doxapram were determined in 13 infants with idiopathic apnea of prematurity uncontrolled by aminophylline and caffeine. Doxapram was maintained for...
Pharmacokinetics of doxapram were determined in 13 infants with idiopathic apnea of prematurity uncontrolled by aminophylline and caffeine. Doxapram was maintained for 72-96 h at a constant infusion rate of 2-2.5 mg/kg/h. Plasma doxapram levels were measured by gas liquid chromatography. The infants studied had a birth weight of 1,247 +/- 240 g (mean +/- SD), a gestational age of 29.4 +/- 2 weeks and were 9.9 +/- 6 days old. Steady-state plasma doxapram levels reached by all infants averaged 5.8 +/- 1.8 mg/l. Half-life was 6.6 +/- 5.7 h, plasma clearance 0.44 +/- 0.1 litres/kg/h, and calculated volume of distribution 4 +/- 2.7 litres/kg. Doxapram controlled apnea successfully in 12 of 13 babies. A significant fall in PaCO2 and reduction in the rate of apnea was seen within 6-8 h with corresponding doxapram levels of 3.7 +/- 1.8 mg/l. The factors influencing the pharmacokinetics of doxapram in newborns are presently unknown.
Topics: Apnea; Doxapram; Female; Half-Life; Humans; Infant, Newborn; Infant, Premature, Diseases
PubMed: 3371147
DOI: 10.1159/000457668 -
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