Dopram (doxapram) / Kissei - LARVOL DELTA

Study to Investigate the Safety, Tolerability and Pharmacokinetics of QEV-817 Oral Suspension (clinicaltrials.gov) - P1 | N=8 | Not yet recruiting | Sponsor: Quivive Pharma, Inc.

New P1 trial

The effects of doxapram and its potential interactions with K2P channels in experimental model preparations. (PubMed, J Comp Physiol A Neuroethol Sens Neural Behav Phys) - "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)."

Journal

A dose-ranging evaluation of inhaled atomized perfluorocarbon for partial liquid ventilation in spontaneously-breathing non-intubated preterm lambs with respiratory distress. (PAS 2024) - "Following intravenous caffeine and doxapram, lambs were extubated and breathed spontaneously with CPAP and supportive breaths provided via binasal cannulae... PFOB administration had no effect on arterial blood pressure or heart rate. There was no difference between study groups with respect to arterial PO2, PCO2, or alveolar-arterial PO2 gradient. Final pulmonary compliance was higher in the 5 and 10 ml/kg groups (4.68 ± 0.52 and 5.60 ± 0.22 ml⋅cmH2O -1⋅kg-1, respectively) compared to the 0 and 2 ml/kg groups (2.65 ± 0.28 and 2.80 ± 0.47 ml⋅cmH2O -1⋅kg-1, respectively, n = 5 per group)."

Prematurity • Acute Respiratory Distress Syndrome • Respiratory Diseases

Doxapram for apnea of prematurity - the importance of maintaining equipoise. (PubMed, Arch Dis Child Fetal Neonatal Ed) - No abstract available

Journal • Critical care

Doxapram Therapy in Preterm Infants (DOXA Trial) (clinicaltrials.gov) - P3 | N=398 | Recruiting | Sponsor: Erasmus Medical Center | Trial completion date: May 2030 ➔ May 2034 | Trial primary completion date: May 2024 ➔ May 2026

Trial completion date • Trial primary completion date • Respiratory Diseases

Doxapram for apnoea of prematurity and neurodevelopmental outcomes at age 5-6 years. (PubMed, Arch Dis Child Fetal Neonatal Ed) - "In children born before 32 weeks' gestation, doxapram treatment for apnoea of prematurity was not associated with neurodevelopmental disabilities."

Journal • Cerebral Palsy • CNS Disorders • Developmental Disorders • Pediatrics • Psychiatry

Clinical Dilemma Involving Treatments for Very Low-Birth-Weight Infants and the Potential Risk of Necrotizing Enterocolitis: A Narrative Literature Review. (PubMed, J Clin Med) - "Indomethacin (utilized for patent ductus arteriosus) offers benefits but is concerning because of its vasoconstrictive impact on NEC susceptibility...Doxapram (used to treat apnea) poses a risk of gastrointestinal disturbance via gastric acid hypersecretion and circulatory changes...Probiotics for NEC prevention are associated with concerns regarding sepsis and bacteremia. Amid conflicting evidence, this review unveils NEC risk factors related to treatments for VLBW infants, offers a comprehensive overview of the current research, and guides personalized management strategies, thereby elucidating this clinical dilemma."

Journal • Review • Bronchopulmonary Dysplasia • Cardiovascular • Gastrointestinal Disorder • Hematological Disorders • Infectious Disease • Pulmonary Disease • Reperfusion Injury • Respiratory Diseases • Septic Shock

Identification of Potential Inhibitors Targeting GTPase-Kirsten RAt Sarcoma Virus (K-Ras) Driven Cancers via E-Pharmacophore-Based Virtual Screening and Drug Repurposing Approach. (PubMed, Front Biosci (Landmark Ed)) - "We have successfully identified potential inhibitors of the K-Ras protein, laying the groundwork for the development of targeted therapies for cancers driven by K-Ras mutations."

Journal • Preclinical • Oncology • Sarcoma • Solid Tumor • KRAS

Improving rates of successful extubation: Medications. (PubMed, Semin Fetal Neonatal Med) - "Efficacy and safety for doxapram, steroids, adrenaline and salbutamol are summarised...Overall, caffeine is the only drug with a substantial evidence base, proven to increase the likelihood of successful extubation in preterm infants; no drugs are needed to facilitate extubation in most term infants. Future studies might further define the role of caffeine in late preterm infants and evaluate medications for post-extubation stridor, bronchospasm or apnoea not responsive to methylxanthines."

Journal • Review • Inflammation • Pneumonia

Doxapram versus placebo in preterm newborns: a study protocol for an international double blinded multicentre randomized controlled trial (DOXA-trial). (PubMed, Trials) - P3 | "Doxapram has the potential to improve neonatal outcomes by improving respiration, but the safety concerns need to be weighed against the potential risks of invasive mechanical ventilation. It is unknown if the use of doxapram improves the long-term outcome. This forms the clinical equipoise of the current trial. This international, multicentre trial will provide the needed high-quality evidence on the efficacy and safety of doxapram in the treatment of AOP in preterm infants."

Journal • Bronchopulmonary Dysplasia • Cardiovascular • Cerebral Palsy • CNS Disorders • Gastrointestinal Disorder • Ophthalmology • Otorhinolaryngology • Pulmonary Disease • Respiratory Diseases

Doxapram for the prevention and treatment of apnea in preterm infants. (PubMed, Cochrane Database Syst Rev) - "In treating apnea of prematurity, doxapram may slightly reduce failure in apnea reduction when compared to no treatment and there may be little to no difference in side effects against both no treatment and alternative treatment. The evidence is very uncertain about the need for positive pressure ventilation when compared to no treatment or alternative treatment and about failed apnea reduction when used as alternative or adjunct therapy to methylxanthine. For use to prevent reintubation, doxapram may reduce apnea episodes when administered in adjunct to methylxanthine, but with little to no difference in failed extubation. The evidence is very uncertain about doxapram's effect on death when used as adjunct therapy to methylxanthine and about failed extubation when used as alternative or adjunct therapy to methylxanthine. There is a knowledge gap about the use of doxapram as a therapy to prevent apnea. More studies are needed to clarify the role of doxapram in the..."

Journal • Review • Pulmonary Disease • Respiratory Diseases

The Effects of Doxapram Blocking the Response of Gram-Negative Bacterial Toxin (LPS) at Glutamatergic Synapses. (PubMed, Biology (Basel)) - "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."

Gram negative • Journal • Infectious Disease

Pharmacologic interventions for the therapy of postanesthetic shivering in adults: a systematic review and network meta-analysis. (PubMed, Minerva Anestesiol) - "Nefopam, tramadol, pethidine and clonidine are the most effective treatments to stop postanesthetic shivering. The efficacy of doxapram is uncertain since different doses showed contradictory effects and the evidence for methylphenidate is based on a single comparison in only one network. Furthermore, both lack data on side effects. Further studies are needed to clarify the efficacy of dexmedetomidine to treat postanesthetic shivering."

Journal • Retrospective data • Review • Anesthesia • Cardiovascular • Pain

"Site Initiation Visit for the Doxapram Therapy in Preterm Infants %28DOXA Trial%29 @canadianpreemie @EBNEO @EAPSCongress @JENS_Congress @AAPneonatal @brendahylaw @PASMeeting @drbretty @souvik_neo @neo_papers @UofAResearch @HotTopicsNeo @ESPNIC_Society https://t.co/TN7esEoXcG" (@Research4Babies)

Targeting a Non-Opioid Signaling Pathway to Reverse Opioid-Induced Respiratory Depression (CPDD 2023) - "1 Preclinical - In Vitro Aim: The opioid epidemic is a public health crisis with growing numbers of overdose deaths caused by ultrapotent synthetic opioids like fentanyl. The carotid body is a chemosensory organ that senses low blood oxygen to increase ventilation within seconds. Small molecule drugs that stimulate the carotid body (doxapram, almitrine, and GAL-021) have been shown to reverse opioid-induced respiratory depression, but these drugs act on molecules expressed broadly in many tissues and have deleterious side effects or ceiling effects that limit their use. We previously identified a G protein-coupled receptor (mouse Olfr78/human OR51E2) that mediates sensory signaling in the carotid body."

Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Mood Disorders • Psychiatry

The effect of doxapram on survival and APGAR score in newborn puppies delivered by elective caesarean: A randomized controlled trial. (PubMed, J Vet Pharmacol Ther) - "Being a brachycephalic breed was not associated with an increased odds of 7-day mortality (p = .156) but the effect of the baseline APGAR score on the probability of having an APGAR score of ten was higher for brachycephalic than non-brachycephalic breeds (p = .01). There was insufficient evidence that intralingual doxapram provided an advantage (or disadvantage) compared to intralingual saline when used routinely in puppies delivered by elective caesarean and that were not apnoeic."

Clinical • Journal

Bacterial lipopolysaccharide hyperpolarizes the membrane potential and is antagonized by the K2p channel blocker doxapram. (PubMed, Comp Biochem Physiol C Toxicol Pharmacol) - "Currently, blockers of LPS receptors in mammals are unknown; further research on doxapram and other K2p channels is warranted. (220 words)."

Journal • Infectious Disease

"Our Doxapram vs placebo RCT for preterm neonatal apnea initiated in the Netherlands and Belgium is going to be started in Canada! Are you interested to join Canadian sites? @souvik_neo @NICU_Musings #MICYRN @Willem_Pieter @karelallegaert @IKMReiss @rbflint @martinoffringa" (@sinno37222817)

Clinical

Hyperpolarization Induced by Lipopolysaccharides but Not by Chloroform Is Inhibited by Doxapram, an Inhibitor of Two-P-Domain K Channel (K2P). (PubMed, Int J Mol Sci) - "Pre-exposure to doxapram reduces the LPS block of these ionotropic glutamate receptors. Given that the larval Drosophila body wall muscles are depolarized by doxapram and hyperpolarized by chloroform, they offer a model to begin pharmacological profiling of the K2P subtype channels with the potential of identifying blockers for the receptors to mitigate the actions of the Gram-negative endotoxin LPS."

Journal • Infectious Disease

QTc Interval Reference Values and Their (Non)-Maturational Factors in Neonates and Infants: A Systematic Review. (PubMed, Children (Basel)) - "Cisapride, domperidone and doxapram result in QTc prolongation in neonates. Further research in this age category is needed to improve primary screening practices and QTcthresholds, earlier detection of risk factors and precision pharmacovigilance."

Journal • Review • Atrial Fibrillation • Cardiovascular • Heart Failure

The effects of doxapram (blocker of K2p channels) on resting membrane potential and synaptic transmission at the Drosophila neuromuscular junction. (PubMed, Comp Biochem Physiol C Toxicol Pharmacol) - "Verapamil (1 and 10 mM) paralleled the action of 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."

Journal

"Now would that be the doxapram or the ApC?!" (@Pipes_n_pumps)

"EDITOR'S CHOICE: Can repurposing #doxapram yield a promising new #antiarrhythmic drug to treat #AFib? Investigating TASK-1 potassium channel inhibition as a novel pharmacological strategy https://t.co/bE6HtdK84R @ESC_Journals @escardio #EPeeps #AF #CardiovascularResearch" (@CVR_TomaszGuzik)

Cardiovascular

Oxygen saturation histogram classification system to evaluate response to doxapram treatment in preterm infants. (PubMed, Pediatr Res) - "The SpO histogram classification system provides a tool for quantifying response to doxapram therapy. The classification system allowed estimation of the probability of invasive mechanical ventilation requirement, already within a few hours of treatment. The SpO histogram classification system allows an objective bedside assessment of the oxygenation status of the preterm infant, making it possible to assess the changes in oxygenation status in response to respiratory interventions."

Journal

"Today we reached N = 50 in the Doxapram trial (RCT doxapram vs placebo next to caffeine for apnea in preterm infants) !!! Great efforts and achievement of many Dutch and Belgian NICUs!! #N3 @karelallegaert @IKMReiss @hniemarkt @Willem_Pieter @emwbk @mjnlbenders @ZonMw @rbflint" (@sinno37222817)

Clinical