-
F1000prime Reports 2014The human body is critically dependent on the ventilatory control system for adequate uptake of oxygen and removal of carbon dioxide (CO2). Potent opioid analgesics,... (Review)
Review
The human body is critically dependent on the ventilatory control system for adequate uptake of oxygen and removal of carbon dioxide (CO2). Potent opioid analgesics, through their actions on μ-opioid receptor (MOR) expressed on respiratory neurons in the brainstem, depress ventilation. Opioid-induced respiratory depression (OIRD) is potentially life threatening and the cause of substantial morbidity and mortality. One possible way of prevention of OIRD is by adding a respiratory stimulant to the opioid treatment, which through activation of non-opioidergic pathways will excite breathing and consequently will offset OIRD and should not affect analgesia. Various new respiratory stimulants are currently under investigation including (a) potassium channel blockers acting at the carotid bodies, and (b) ampakines and (c) serotonin receptor agonists acting within the brainstem. (a) GAL-021 targets BKCa-channels. Initial animal and human experimental evidence indicates that this potassium channel blocker is a potent respiratory stimulant that reverses OIRD without affecting antinociception. GAL021 is safe and better tolerated than the older K(+)-channel blocker doxapram and more efficacious in its effect on respiration. (b) Ampakines modulate glutamatergic respiratory neurons in brainstem respiratory centers. Various ampakines have been studied showing their ability to increase respiratory drive during OIRD by increasing respiratory rate. Currently, CX717 is the most promising ampakine for use in humans as it is safe and does not affect opioid analgesia. (c) While animal studies show that serotonin receptor agonists increase respiratory drive via activation of serotonin receptors in brainstem respiratory centers, human studies are without success. Further clinical studies are required to improve our care of patients that are treated with potent opioid analgesics. The use of non-opioid adjuvants may reduce the probability of OIRD but does never relieve us of our duty to continuously monitor these patients, irrespective whether they are treated in-house or in an ambulatory setting.
PubMed: 25343036
DOI: 10.12703/P6-79 -
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 -
Journal of Equine Veterinary Science Apr 2022This randomized double-blinded study evaluated the recovery from isoflurane anesthesia in horses receiving doxapram and xylazine. 6 horses were anesthetized 4 times...
This randomized double-blinded study evaluated the recovery from isoflurane anesthesia in horses receiving doxapram and xylazine. 6 horses were anesthetized 4 times (minimum of 2-week washout period). Anesthesia was performed with xylazine (0.6 mg/kg), ketamine (2.2 mg/kg), midazolam (0.1 mg/kg), and maintained with isoflurane for 90 minutes. At recovery, horses received one of the following randomized treatments: RX: xylazine (0.2 mg/kg), RXD1: xylazine (0.2 mg/kg) and doxapram (0.1 mg/kg), RXD2: xylazine (0.2 mg/kg) and doxapram (0.2 mg/kg), or RS: saline. Recoveries were rope-assisted and evaluated with a descriptive qualitative scale. Heart rate, respiratory frequency (f), and blood gas analysis were evaluated at 5 minutes intervals while the horse allowed. Data were analyzed with ANOVA or Friedman test (P < .05). Times to sternal (minutes) were RX: 40.5 ± 12.3, RXD1: 25.8 ± 11.5, RXD2: 31.4 ± 7.0, and RS: 33.4 ± 5.3, and were not different. Times to standing (minutes) were RX: 41.0 ± 9.9, RXD1: 33.5 ± 6.2, RXD2: 40.0 ± 11.3, and RS: 36.3 ± 9.9, and were not different. Heart rate decrease over time within RXD1 and RXD2 (T0 = 47 ± 15 and 47 ± 15, T5 = 38 ± 8 and 38 ± 8, T10 = 39 ± 4 and 36 ± 6, respectively), but was not different among groups. There was no difference in f among groups or over time. There was no difference in recovery scores among groups. In conclusion, administration of doxapram to isoflurane-anesthetized horses did not change recovery time or quality.
Topics: Anesthesia Recovery Period; Anesthetics, Inhalation; Animals; Doxapram; Horses; Isoflurane; Xylazine
PubMed: 35074399
DOI: 10.1016/j.jevs.2022.103872 -
Cardiovascular Research Jun 2022
Topics: Atrial Fibrillation; Doxapram; Humans; Potassium Channels
PubMed: 35425974
DOI: 10.1093/cvr/cvac044 -
Neonatology 2019Doxapram is a treatment option for severe apnea of prematurity (AOP). However, the effect of doxapram on the diaphragm, the main respiratory muscle, is not known. (Observational Study)
Observational Study
BACKGROUND
Doxapram is a treatment option for severe apnea of prematurity (AOP). However, the effect of doxapram on the diaphragm, the main respiratory muscle, is not known.
OBJECTIVES
To investigate the effect of doxapram on diaphragmatic activity measured with transcutaneous electromyography of the diaphragm (dEMG).
METHODS
A pilot study was conducted in a tertiary neonatal intensive care unit. Diaphragmatic activity was measured from 30 min before up to 3 h after the start of doxapram treatment. dEMG parameters were compared to baseline (5 min before doxapram treatment) and at 15, 60, 120 and 180 min after the start of doxapram infusion.
RESULTS
Eleven preterm infants were included with a mean gestational age of 25.5 ± 1.2 weeks and birth weight of 831 ± 129 g. The amplitudedEMG, peakdEMG and tonicdEMG values did not change in the 3 h after the start of doxapram infusion compared to baseline. Clinically, the number of apnea episodes in the 24 h after doxapram treatment decreased significantly.
CONCLUSION
Doxapram infusion does not alter diaphragmatic activity measured with transcutaneous dEMG in preterm infants with AOP, indicating that its working mechanism is primarily on respiratory drive and not on respiratory muscle activity.
Topics: Apnea; Birth Weight; Diaphragm; Doxapram; Electromyography; Female; Gestational Age; Humans; Infant, Extremely Low Birth Weight; Infant, Extremely Premature; Infant, Newborn; Infant, Premature, Diseases; Intensive Care Units, Neonatal; Male; Netherlands; Pilot Projects; Prospective Studies; Respiratory System Agents
PubMed: 30352445
DOI: 10.1159/000493359 -
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 -
Cardiovascular Research Jun 2022TASK-1 (K2P3.1) two-pore-domain potassium channels are atrial-specific and significantly up-regulated in atrial fibrillation (AF) patients, contributing to AF-related...
AIMS
TASK-1 (K2P3.1) two-pore-domain potassium channels are atrial-specific and significantly up-regulated in atrial fibrillation (AF) patients, contributing to AF-related electrical remodelling. Inhibition of TASK-1 in cardiomyocytes of AF patients was shown to counteract AF-related action potential duration shortening. Doxapram was identified as a potent inhibitor of the TASK-1 channel. In this study, we investigated the antiarrhythmic efficacy of doxapram in a porcine model of AF.
METHODS AND RESULTS
Doxapram successfully cardioverted pigs with artificially induced episodes of AF. We established a porcine model of persistent AF in domestic pigs via intermittent atrial burst stimulation using implanted pacemakers. All pigs underwent catheter-based electrophysiological investigations prior to and after 14 days of doxapram treatment. Pigs in the treatment group received intravenous administration of doxapram once per day. In doxapram-treated AF pigs, the AF burden was significantly reduced. After 14 days of treatment with doxapram, TASK-1 currents were still similar to values of sinus rhythm animals. Doxapram significantly suppressed AF episodes and normalized cellular electrophysiology by inhibition of the TASK-1 channel. Patch-clamp experiments on human atrial cardiomyocytes, isolated from patients with and without AF could reproduce the TASK-1 inhibitory effect of doxapram.
CONCLUSION
Repurposing doxapram might yield a promising new antiarrhythmic drug to treat AF in patients.
Topics: Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Doxapram; Heart Atria; Humans; Nerve Tissue Proteins; Potassium Channel Blockers; Potassium Channels, Tandem Pore Domain; Swine
PubMed: 34028533
DOI: 10.1093/cvr/cvab177 -
Behavioural Pharmacology Apr 2021Panic disorder can be categorized into the nonrespiratory or the respiratory subtypes, the latter comprising dyspnea, shortness of breath, chest pain, feelings of...
Panic disorder can be categorized into the nonrespiratory or the respiratory subtypes, the latter comprising dyspnea, shortness of breath, chest pain, feelings of suffocation, and paresthesias. Doxapram is an analeptic capable of inducing panic attacks with respiratory symptoms in individuals diagnosed with the disorder; however, its neuroanatomical targets and its effects on experimental animals remain uncharacterized. One of the brain regions proposed to trigger panic attacks is the midbrain periaqueductal gray (PAG). Therefore, in this study, we evaluated the effects of doxapram in Fos (c-Fos) protein expression in the PAG and characterized its cardiorespiratory and behavioral effects on the elevated T maze and in the conditioned place aversion (CPA) paradigms. Doxapram increased Fos expression in different columns of the PAG, increased respiratory frequency, decreased heart rate, and increased arterial pressure when injected via intravenous route. Alprazolam, a panicolytic benzodiazepine, injected via intraperitoneal route, decreased respiratory frequency, whereas URB597, an anandamide hydrolysis inhibitor injected via intraperitoneal route, was ineffective. Doxapram injected via intraperitoneal route induced an anxiogenic-like effect in the elevated T-maze model; however, it failed to induce CPA. This study suggests that the cardiorespiratory and behavioral effects of doxapram in rodents serve as an experimental model that can provide insights into the neurobiology of panic attacks.
Topics: Administration, Intravenous; Alprazolam; Animals; Benzamides; Carbamates; Central Nervous System Stimulants; Disease Models, Animal; Doxapram; Male; Maze Learning; Panic Disorder; Periaqueductal Gray; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar
PubMed: 33136614
DOI: 10.1097/FBP.0000000000000594 -
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 -
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