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Veterinary Anaesthesia and Analgesia May 2018To compare the effects of alfaxalone and propofol, with and without acepromazine and butorphanol followed by doxapram, on laryngeal motion and quality of laryngeal... (Comparative Study)
Comparative Study Randomized Controlled Trial
OBJECTIVE
To compare the effects of alfaxalone and propofol, with and without acepromazine and butorphanol followed by doxapram, on laryngeal motion and quality of laryngeal examination in dogs.
STUDY DESIGN
Randomized, crossover, blinded study.
ANIMALS
Ten female Beagle dogs, aged 11-13 months and weighing 7.2-8.6 kg.
METHODS
The dogs were administered four intravenous (IV) treatments: alfaxalone (ALF), alfaxalone+acepromazine and butorphanol (ALF-AB), propofol (PRO) and propofol+AB (PRO-AB). AB doses were standardized. Dogs were anesthetized 5 minutes later by administration of alfaxalone or propofol IV to effect. Arytenoid motion during maximal inspiration and expiration was captured on video before and after IV doxapram (0.25 mg kg). The change in rima glottidis surface area (RGSA) was calculated to measure arytenoid motion. An investigator blinded to the treatment scored laryngeal examination quality.
RESULTS
A 20% increase in RGSA was the minimal arytenoid motion that was detectable. RGSA was significantly less in ALF before doxapram compared with all other treatments. A <20% increase in RGSA was measured in eight of 10 dogs in PRO and in all dogs in ALF before doxapram. After doxapram, RGSA was significantly increased for PRO and ALF; however, 20% of dogs in PRO and 50% of dogs in ALF still had <20% increase in RGSA. A <20% increase in RGSA was measured in five of 10 dogs in PRO-AB and ALF-AB before doxapram. All dogs in PRO-AB and ALF-AB with <20% increase in RGSA before doxapram had ≥20% increase in RGSA after doxapram. Examination quality was significantly better in PRO-AB and ALF-AB.
CONCLUSIONS AND CLINICAL RELEVANCE
The use of acepromazine and butorphanol improved the quality of laryngeal examination. Any negative impact on arytenoid motion caused by these premedications was overcome with doxapram. Using either propofol or alfaxalone alone is not recommended for the evaluation of arytenoid motion.
Topics: Acepromazine; Anesthesia; Anesthetics; Anesthetics, Combined; Animals; Butorphanol; Cross-Over Studies; Dog Diseases; Dogs; Doxapram; Female; Laryngoscopy; Larynx; Physical Examination; Pregnanediones; Propofol; Vocal Cord Paralysis
PubMed: 29426677
DOI: 10.1016/j.vaa.2017.08.014 -
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 -
Biomedical Chromatography : BMC Oct 2018A simple and specific UPLC-MS/MS method was developed and validated for simultaneous quantification of fentanyl, sufentanil, cefazolin, doxapram and its active... (Observational Study)
Observational Study
A simple and specific UPLC-MS/MS method was developed and validated for simultaneous quantification of fentanyl, sufentanil, cefazolin, doxapram and its active metabolite keto-doxapram. The internal standard was fentanyl-d5 for all analytes. Chromatographic separation was achieved with a reversed-phase Acquity UPLC HSS T3 column with a run-time of only 5.0 min per injected sample. Gradient elution was performed with a mobile phase consisting of ammonium acetate or formic acid in Milli-Q ultrapure water or in methanol with a total flow rate of 0.4 mL min . A plasma volume of only 50 μL was required to achieve adequate accuracy and precision. Calibration curves of all five analytes were linear. All analytes were stable for at least 48 h in the autosampler. The method was validated according to US Food and Drug Administration guidelines. This method allows quantification of fentanyl, sufentanil, cefazolin, doxapram and keto-doxapram, which is useful for research as well as therapeutic drug monitoring, if applicable. The strength of this method is the combination of a small sample volume, a short run-time, a deuterated internal standard, an easy sample preparation method and the ability to simultaneously quantify all analytes in one run.
Topics: Cefazolin; Chromatography, High Pressure Liquid; Doxapram; Drug Stability; Fentanyl; Humans; Infant, Newborn; Limit of Detection; Linear Models; Prospective Studies; Reproducibility of Results; Tandem Mass Spectrometry
PubMed: 29768657
DOI: 10.1002/bmc.4290 -
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 -
Comparative Biochemistry and... Jan 2023The resting membrane potential of most cells is maintained by potassium K2p channels. The pharmacological profile and distribution of various K2p channel subtypes in...
The resting membrane potential of most cells is maintained by potassium K2p channels. The pharmacological profile and distribution of various K2p channel subtypes in organisms are still being investigated. The Drosophila genome contains 11 subtypes; however, their function and expression profiles have not yet been determined. Doxapram is clinically used to enhance respiration in humans and blocks the acid-sensitive K2p TASK subtype in mammals. The resting membrane potential of larval Drosophila muscle and synaptic transmission at the neuromuscular junction are pH sensitive. The present study investigated the effects of doxapram on membrane potential and synaptic transmission using intracellular recordings of larval Drosophila muscles. Doxapram (1 mM and 10 mM) depolarizes the muscle and appears to depolarize motor neurons, causing an increase in the frequency of spontaneous quantal events and evoked excitatory junction potentials. Verapamil (1 and 10 mM) paralleled the action of doxapram. These changes were matched by an extracellular increase in KCl (50 mM) and blocked by Cd. It is assumed that the motor nerve depolarizes to open voltage-gated Ca channels in presynaptic nerve terminals because of exposure to doxapram. These findings are significant for building models to better understand the function of pharmacological agents that affect K2p channels and how K2p channels contribute to the physiology of tissues. Drosophila offers a genetically amenable model that can alter the tissue-specific expression of K2p channel subtypes to simulate known human diseases related to this family of channels.
Topics: Animals; Humans; Membrane Potentials; Drosophila; Doxapram; Neuromuscular Junction; Synaptic Transmission; Potassium Channels; Mammals
PubMed: 36306997
DOI: 10.1016/j.cbpc.2022.109497 -
Acta Paediatrica (Oslo, Norway : 1992) May 2017Using doxapram to treat neonates with apnoea of prematurity might avoid the need for endotracheal intubation and invasive ventilation. We studied whether doxapram...
AIM
Using doxapram to treat neonates with apnoea of prematurity might avoid the need for endotracheal intubation and invasive ventilation. We studied whether doxapram prevented the need for intubation and identified the predictors of the success.
METHODS
This was a retrospective study of preterm infants born from January 2006 to August 2014 who received oral or intravenous doxapram. Success was defined as no need for endotracheal intubation, due to apnoea, during doxapram therapy. Univariable and multivariable logistic regression analyses identified predictors of success during the first 48 hours of doxapram therapy.
RESULTS
Data on 203 patients with a median gestational age of 26.1 (interquartile range 25.1-27.4) weeks were analysed. During the first 48 hours of doxapram therapy, 157 (77%) patients did not need endotracheal intubation and 127 (63%) patients were successfully treated over the entire treatment course. The median postnatal age at the start of doxapram therapy was 20 days (interquartile range 12-30). Postnatal age and a lower fraction of inspired oxygen at the start of doxapram therapy were significant predictors of success (odds ratio 0.964, 95% confidence interval 0.938-0.991, p = 0.001).
CONCLUSION
Oral and intravenous doxapram effectively treated most cases of apnoea in preterm infants, avoiding the need for intubation.
Topics: Apnea; Doxapram; Female; Humans; Infant, Newborn; Infant, Premature; Intubation, Intratracheal; Male; Respiratory System Agents; Retrospective Studies
PubMed: 28130789
DOI: 10.1111/apa.13761 -
Bioanalysis Mar 2017Doxapram, a respiratory stimulant, is used to treat apnea. A reliable method of determining doxapram in blood is required for monitoring purposes.
AIM
Doxapram, a respiratory stimulant, is used to treat apnea. A reliable method of determining doxapram in blood is required for monitoring purposes.
RESULTS
Doxapram, keto-doxapram (active metabolite) and propranolol (internal standard) were extracted from human serum by protein precipitation and plate filtration. Molecular ions were generated by electrospray ionization in positive ion mode, and the ions were analyzed using a triple-quadrupole mass spectrometer. The calibration curves were linear from 20 to 5000 ng/ml. The method was validated and the selectivity, reproducibility and stability met the acceptance criteria.
CONCLUSION
An LC-MS/MS method was successfully developed for determining doxapram and keto-doxapram in human serum. The method can be used to monitor doxapram and keto-doxapram concentrations in blood.
Topics: Calibration; Chromatography, Liquid; Doxapram; Drug Monitoring; Drug Stability; Humans; Limit of Detection; Propranolol; Reference Standards; Reproducibility of Results; Tandem Mass Spectrometry
PubMed: 28225296
DOI: 10.4155/bio-2016-0267 -
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 -
Physiological Reports Sep 2018Sensing of hypoxia and acidosis in arterial chemoreceptors is thought to be mediated through the inhibition of TASK and possibly other (e.g., BK ) potassium channels...
Sensing of hypoxia and acidosis in arterial chemoreceptors is thought to be mediated through the inhibition of TASK and possibly other (e.g., BK ) potassium channels which leads to membrane depolarization, voltage-gated Ca-entry, and neurosecretion. Here, we investigate the effects of pharmacological inhibitors on TASK channel activity and [Ca ] -signaling in isolated neonatal rat type-1 cells. PK-THPP inhibited TASK channel activity in cell attached patches by up to 90% (at 400 nmol/L). A1899 inhibited TASK channel activity by 35% at 400 nmol/L. PK-THPP, A1899 and Ml 365 all evoked a rapid increase in type-1 cell [Ca ] . These [Ca ] responses were abolished in Ca -free solution and greatly attenuated by Ni (2 mM) suggesting that depolarization and voltage-gated Ca -entry mediated the rise in [Ca ] Doxapram (50 μmol/L), a respiratory stimulant, also inhibited type-1 cell TASK channel activity and increased [Ca ] . We also tested the effects of combined inhibition of BK and TASK channels. TEA (5 mmol/L) slightly increased [Ca ] in the presence of PK-THPP and A1899. Paxilline (300 nM) and iberiotoxin (50 nmol/L) also slightly increased [Ca ] in the presence of A1899 but not in the presence of PK-THPP. In general [Ca ] responses to TASK inhibitors, alone or in combination with BK inhibitors, were smaller than the [Ca ] responses evoked by hypoxia. These data confirm that TASK channel inhibition is capable of evoking membrane depolarization and robust voltage-gated Ca -entry but suggest that this, even with concomitant inhibition of BK channels, may be insufficient to account fully for the [Ca ] -response to hypoxia.
Topics: Animals; Animals, Newborn; Benzamides; Benzeneacetamides; Calcium Signaling; Carotid Body; Doxapram; HEK293 Cells; Humans; Nerve Tissue Proteins; Potassium Channels, Tandem Pore Domain; Rats; Rats, Sprague-Dawley; Respiratory System Agents
PubMed: 30284397
DOI: 10.14814/phy2.13876